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Publisher: Oxford University Press   (Total: 370 journals)

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Showing 1 - 200 of 370 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 9, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 59, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 85, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 17, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 148, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 39, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 171, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 18)
American J. of Legal History     Full-text available via subscription   (Followers: 6, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 23)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 28, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 50, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 19, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 52, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 13)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 27, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 45, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 51, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 273, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 19, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 30, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 156, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 65, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 63, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 45, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 35, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 27, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 547, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 85, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 27)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 59, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 10, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 11, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal   (Followers: 1)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 12, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 43, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 17, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 21, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 9, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 24, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 60, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 24, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 8, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 26)
Current Zoology     Full-text available via subscription   (Followers: 1, SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 13)
Diplomatic History     Hybrid Journal   (Followers: 20, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 15, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 37, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 51, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 13, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 28, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 10, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 50, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 8, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 7, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 8, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 168, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 23, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 11, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 28, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 41, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 12, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 9, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 21, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 26, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 22, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 32, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 20, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 12, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 34, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 26, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 50, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 13, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 21, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 21, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 27, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 26, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 79, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 17, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 61, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 54, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 11)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 1, SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 7, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 32, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 5, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 52, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 30)
Intl. Health     Hybrid Journal   (Followers: 5, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 34, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 60, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 149, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 4, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 29, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 9, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 34, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 13, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 31, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 18, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 40, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 18, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 44, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 13, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 17, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 36, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 13, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 43, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 10, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 9, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 16, SJR: 0.166, h-index: 14)
J. of Economic Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.894, h-index: 76)
J. of Economic Geography     Hybrid Journal   (Followers: 24, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 24, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 20)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 22, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 4)
J. of Heredity     Hybrid Journal   (Followers: 4, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 20, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 39, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 9, SJR: 0.388, h-index: 31)

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Journal Cover Human Reproduction
  [SJR: 2.271]   [H-I: 179]   [79 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0268-1161 - ISSN (Online) 1460-2350
   Published by Oxford University Press Homepage  [370 journals]
  • Early first trimester uteroplacental flow and the progressive
           disintegration of spiral artery plugs: new insights from contrast-enhanced
           ultrasound and tissue histopathology
    • Authors: Roberts V; Morgan T, Bednarek P, et al.
      Abstract: STUDY QUESTIONDoes the use of a vascular contrast agent facilitate earlier detection of maternal flow to the placental intervillous space (IVS) in the first trimester of pregnancy'SUMMARY ANSWERMicrovascular filling of the IVS was demonstrated by contrast-enhanced ultrasound from 6 weeks of gestation onwards, earlier than previously believed.WHAT IS KNOWN ALREADYDuring placental establishment and remodeling of maternal spiral arteries, endovascular trophoblast cells invade and accumulate in the lumen of these vessels to form ‘trophoblast plugs’. Prior evidence from morphological and Doppler ultrasound studies has been conflicting as to whether the spiral arteries are completely plugged, preventing maternal blood flow to the IVS until late in the first trimester.STUDY DESIGN, SIZE, DURATIONUteroplacental flow was examined across the first trimester in human subjects given an intravenous infusion of lipid-shelled octofluoropropane microbubbles with ultrasound measurement of destruction and replenishment kinetics. We also performed a comprehensive histopathological correlation using two separately archived uteroplacental tissue collections to evaluate the degree of spiral artery plugging and evaluate remodeling of the upstream myometrial radial and arcurate arteries.PARTICIPANTS/MATERIALS, SETTING, METHODSPregnant women (n = 34) were recruited in the first trimester (range: 6+3 to 13+6 weeks gestation) for contrast-enhanced ultrasound studies with destruction-replenishment analysis of signal intensity for assessment of microvascular flux rate. Histological samples from archived in situ (Boyd Collection, n = 11) and fresh first, second, and third trimester decidual and post-hysterectomy uterine specimens (n = 16) were evaluated by immunohistochemistry (using markers of epithelial, endothelial and T-cells, as well as cell adhesion and proliferation) and ultrastructural analysis.MAIN RESULTS AND THE ROLE OF CHANCEContrast agent entry into the IVS was visualized as early as 6+3 weeks of gestation with some variability in microvascular flux rate noted in the 6–7+6 week samples. Spiral artery plug canalization was observed from 7 weeks with progressive disintegration thereafter. Of note, microvascular flux rate did not progressively increase until 13 weeks, which suggests that resistance to maternal flow in the early placenta may be mediated more proximally by myometrial radial arteries that begin remodeling at the end of the first trimester.LIMITATIONS REASONS FOR CAUTIONGestational age was determined by crown-rump length measurements obtained by transvaginal ultrasound on the day of contrast-enhanced imaging studies, which may explain the variability in the earliest gestational age samples due to the margin of error in this type of measurement.WIDER IMPLICATIONS OF THE FINDINGSOur comprehensive in situ histological analysis, in combination with the use of an in vivo imaging modality that has the sensitivity to permit visualization of microvascular filling, has allowed us to reveal new evidence in support of increasing blood flow to the IVS from 6 weeks of gestation. Histologic review suggested the mechanism may be blood flow through capillary-sized channels that form through the loosely cohesive ‘plugs’ by 7 weeks gestation. However, spiral artery remodeling on its own did not appear to explain why there is significantly more blood flow at 13 weeks gestation. Histologic studies suggest it may be related to radial artery remodeling, which begins at the end of the first trimester.STUDY FUNDING/COMPETING INTEREST(S)This project was supported by the Oregon Health and Science University Knight Cardiovascular Institute, Center for Developmental Health and the Struble Foundation. There are no competing interests.
      PubDate: 2017-11-10
  • Antioxidants improve IVF outcome and subsequent embryo development in the
    • Authors: Truong T; Gardner D.
      Abstract: STUDY QUESTIONWhat is the effect of a combination of three antioxidants (Acetyl-L-Carnitine, N-Acetyl-L-Cysteine and α-Lipoic Acid), present in IVF medium during mouse oocyte and sperm collection, on fertilization and subsequent IVF embryo development'SUMMARY ANSWERA combination of antioxidants resulted in faster developmental times from the 2-cell stage through to expanded blastocyst stage, accompanied by a significant increase in blastocyst cell number and a reduction of intracellular hydrogen peroxide (H2O2) levels.WHAT IS KNOWN ALREADYThe antioxidant combination Acetyl-L-Carnitine, N-Acetyl-L-Cysteine and α-Lipoic Acid, when present in embryo culture media, has a significant beneficial effect on in vitro fertilized mouse pronucleate oocyte development, especially under oxidative stress.STUDY DESIGN, SIZE, DURATIONIVF was conducted with combined antioxidants supplemented in IVF medium that was used for mouse oocyte collection and fertilization (oocyte IVF medium, 4 h exposure) and sperm collection and preparation (sperm IVF medium, 1 h exposure).PARTICIPANTS/MATERIALS, SETTINGS, METHODSIVF was conducted under 20% oxygen, in the presence or absence of a combination of antioxidants (10 μM Acetyl-L-Carnitine, 10 μM N-Acetyl-L-Cysteine, 5 μM α-Lipoic Acid) and resultant embryos cultured with and without antioxidants under 20% oxygen. Subsequently, the effects of antioxidants on either oocytes or sperm was evaluated. Embryo development was analysed through time-lapse microscopy followed by differential nuclear staining to determine cell allocation in the blastocyst. Intracellular levels of H2O2 were assessed using an aryl boronate probe after 4 h of incubation with antioxidants. Controls were gametes and embryos that had no antioxidants in the medium. In a separate series of experiments, pronucleate oocytes were collected in handling medium with and without antioxidants for 20 min and subsequent cell numbers analysed.MAIN RESULTS AND THE ROLE OF CHANCEAntioxidant treatment during both IVF and culture resulted in significantly faster development times to two cell cleavage (P < 0.01), which continued through to the expanded blastocyst stage (P < 0.05). Resultant blastocysts had a significant increase in both trophectoderm (TE) cell numbers, inner cell mass (ICM) and total cell numbers (P < 0.001). The addition of antioxidants to IVF medium or embryo culture media exclusively also resulted in a significant increase in both blastocyst TE and ICM numbers leading to an increase in total cell numbers (P < 0.001). Antioxidant supplementation of either oocyte IVF medium alone, or in both oocyte and sperm IVF medium, lead to significantly faster times to two cell cleavage, which continued through to the expanded blastocyst stage. Blastocyst cell number in both these groups had significantly higher TE cell numbers resulting in an increase in total cell numbers. In contrast, there were no differences in embryo developmental rates and blastocyst cell number when antioxidants were present only in the sperm IVF medium. Levels of H2O2 were significantly reduced in pronucleate oocytes that were cultured in the presence of antioxidants (P < 0.001) compared to control, untreated embryos. Similarly, pronucleate oocytes treated with the combined antioxidants during pronucleate oocyte collection resulted in significantly increased blastocyst ICM numbers compared with controls (P < 0.05).LIMITATIONS, REASONS FOR CAUTIONEmbryo development was only examined in the mouse.WIDER IMPLICATIONS OF THE FINDINGSThese findings suggest that supplementation of antioxidants to the IVF medium, as well as to embryo culture media, may further assist in maintaining the viability of human embryos in ART, conceivably through the reduction of oxidative stress.STUDY FUNDING/COMPETING INTEREST(S)This work was funded by a research grant from Vitrolife AB (Sweden). The authors have no conflict of interest to declare.
      PubDate: 2017-11-10
  • The incidence and origin of segmental aneuploidy in human oocytes and
           preimplantation embryos
    • Authors: Babariya D; Fragouli E, Alfarawati S, et al.
      Abstract: STUDY QUESTIONWhat is the incidence, origin and clinical significance of segmental aneuploidy in human oocytes and preimplantation embryos'SUMMARY ANSWERSegmental aneuploidy occurs at a considerable frequency in preimplantation embryos with a majority being mitotic in origin.WHAT IS KNOWN ALREADYIn recent years, accurate techniques for the detection of aneuploidy in single cells have been developed. Research using such methods has confirmed that aneuploidy is a common feature of human oocytes and preimplantation embryos. However, thus far research has mainly focused on loss or gain of whole chromosomes. We utilized sensitive molecular methods to study another important form of cytogenetic abnormality at the earliest stages of human development, namely segmental aneuploidy.STUDY DESIGN, SIZE, DURATIONChromosomal copy number data was obtained from oocytes and embryos of 635 IVF patients, who requested chromosome screening for various reasons, most commonly for advanced maternal age or previously unsuccessful IVF treatments. A total of 3541 samples comprising of 452 human oocytes, 1762 cleavage stage and 1327 blastocyst stage embryos were investigated in the present study.PARTICIPANTS/MATERIALS, SETTING, METHODSWhole genome amplification (Sureplex, Illumina) was performed on cells biopsied from oocytes and embryos of IVF patients who requested chromosome screening. The samples were subsequently processed and analyzed for their chromosome complement using microarray comparative genomic hybridization (aCGH), (Illumina, Cambridge, UK).MAIN RESULTS AND THE ROLE OF CHANCESegmental abnormalities, involving loss or gain of chromosomal fragments in excess of 15 Mb, were found to occur at a high frequency. The incidence of such abnormalities was 10.4% in oocytes, but this increased dramatically during the first 3 days of embryonic development (24.3%), before starting to decline as embryos reached the final (blastocyst) stage of preimplantation development (15.6%). While some segmental errors were clearly of meiotic origin, most appear to arise during the first few mitoses following fertilization. The reduction in frequency at the blastocyst stage suggests that many cells/embryos affected by segmental abnormalities are eliminated (e.g. via arrest of the affected embryos or apoptosis of abnormal cells). Interestingly, sites of chromosome breakage associated with segmental aneuploidy were not entirely random but tended to occur within distinct chromosomal regions. Some of the identified hotspots correspond to known fragile sites while others may be considered novel and may be specific to gametogenesis and/or embryogenesis.LIMITATIONS REASONS FOR CAUTIONThe cytogenetic analysis was performed on biopsies of embryos, which might not be representative of the true incidence of mosaic segmental aneuploidy of the entire embryo.WIDER IMPLICATIONS OF THE FINDINGSThe findings of this study are valuable for understanding the origin of subchromosomal duplications and deletions, a clinically important class of abnormalities that are a common cause of congenital abnormalities and miscarriage. Furthermore, the results provide additional evidence that control of the cell cycle is more relaxed during the first few mitotic divisions following fertilization, permitting DNA double-strand breaks to occur and persist through cell division. The data are also of great relevance for preimplantation genetic testing, where the detection of segmental aneuploidy is currently considered problematic for embryo diagnosis and patient counseling.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by institutional funding (Reprogenetics UK). Additionally, DW is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme. DB was supported by the University of Oxford's Clarendon funding. No conflict of interests to declare.
      PubDate: 2017-11-08
  • Effect of ulipristal acetate and mifepristone at emergency contraception
           dose on the embryo-endometrial attachment using an in vitro human
           trophoblastic spheroid and endometrial cell co-culture model
    • Authors: Li H; Li Y, Li T, et al.
      Abstract: STUDY QUESTIONDo both ulipristal acetate (UPA) and mifepristone inhibit embryo-endometrial attachment at concentrations corresponding to the emergency contraception (EC) dose'SUMMARY ANSWERBoth UPA and mifepristone at concentrations corresponding to the EC dose do not have an inhibitory effect on embryo implantation, although mifepristone at a higher concentration appeared to have such an effect.WHAT IS KNOWN ALREADYLevonorgestrel is commonly used for EC, but it only acts through inhibition of ovulation. UPA and mifepristone have higher efficacy as EC compared to levonorgestrel; while there is some suggestion that mifepristone may interfere with implantation, whether UPA has post-ovulatory action in inhibiting implantation is yet to be confirmed.STUDY DESIGN, SIZE, DURATIONAn in vitro experimental study using trophoblastic spheroids made from JAr cell line as the embryo surrogate, and the Ishikawa cell line and primary human endometrial cells cultured to monolayer as the endometrial surrogate. The primary endometrial cells were collected from nine volunteer women in the mid-luteal phase with consent.PARTICIPANTS/MATERIALS, SETTING, METHODSThe study was conducted in a university gynaecology unit. The JAr and Ishikawa cell lines (or primary endometrial cells) were treated with graded concentrations of UPA (0, 0.04, 0.4 and 4 μM) or mifepristone (0, 0.1, 1 and 10 μM) for 24 h. Embryo-endometrial attachment was studied using an in vitro JAr spheroid-endometrial co-culture model. Expressions of progesterone receptor, β-catenin and glycogen synthase kinase 3 β (GSK-3β) were studied with real-time RT-PCR and Western blotting, respectively.MAIN RESULTS AND THE ROLE OF CHANCEIn the Ishikawa experiments, there was no significant difference in the JAr spheroid attachment rate after treatment with UPA at 0 (93.0%), 0.04 (93.6%), 0.4 (93.4%) and 4 (91.4%) μM concentrations (P > 0.05); the attachment rate was reduced after treatment with mifepristone only at 10 μM (79.8%, P < 0.0001) but not at 0.1 (92.1%) or 1.0 (95.2%) μM concentrations. In the primary endometrial cell experiments, again no significant difference was observed in the JAr spheroid attachment rate after treatment with UPA 4 μM (42.6%) compared to control (46.5%, P > 0.05). Both UPA and mifepristone could significantly up-regulate progesterone receptor expression. There was no significant alteration in expression of β-catenin and GSK-3β after treatment with UPA 4 μM or mifepristone 10 μM (P > 0.05).LIMITATIONS, REASONS FOR CAUTIONThe co-culture model is only a surrogate which may not fully represent the complicated process of embryo implantation in vivo, although there is no existing perfect model for studying implantation in vitro which fully resembles the latter.WIDER IMPLICATIONS OF THE FINDINGSThe lack of inhibitory effect on embryo implantation by UPA and possibly mifepristone at concentrations corresponding to the EC dose is an important information for contraceptive counseling.STUDY FUNDING/COMPETING INTEREST(S)We had free supply of the UPA compound used in this study from Laboratoire HRA Pharma. This work was supported by a Seed Fund from the Centre of Reproduction, Development and Growth, Faculty of Medicine, The University of Hong Kong, Hong Kong.
      PubDate: 2017-11-07
  • Individualized FSH dosing based on ovarian reserve testing in women
           starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis
    • Authors: van Tilborg T; Oudshoorn S, Eijkemans M, et al.
      Abstract: STUDY QUESTIONIs there a difference in live birth rate and/or cost-effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment'SUMMARY ANSWERIn women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose.WHAT IS KNOWN ALREADYIn IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists.STUDY DESIGN, SIZE, DURATIONBetween May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11–15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping.PARTICIPANTS/MATERIALS, SETTING, METHODSIn both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti-Müllerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective.MAIN RESULTS AND THE ROLE OF CHANCEWe included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference −0.019 (95% CI, −0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = €275 (95% CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were €35). The analysis based on AMH as a tool for dose individualization suggested comparable results.LIMITATIONS, REASONS FOR CAUTIONDespite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, selective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co-treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response.WIDER IMPLICATIONS OF THE FINDINGSIndividualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). AMH measurements were performed free of charge by Roche Diagnostics. TCT, HLT and SCO received an unrestricted personal grant from Merck BV. AH declares that the department of Obstetrics and Gynecology, University Medical Centre Groningen receives an unrestricted research grant from Ferring pharmaceutics BV, The Netherlands. CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other autors have nothing to declare.TRIAL REGISTRATION NUMBERRegistered at the ICMJE-recognized Dutch Trial Registry ( Registration number: NTR2657.
      PubDate: 2017-11-07
  • Individualized versus standard FSH dosing in women starting IVF/ICSI: an
           RCT. Part 1: The predicted poor responder
    • Authors: van Tilborg T; Torrance H, Oudshoorn S, et al.
      Abstract: STUDY QUESTIONDoes an increased FSH dose result in higher cumulative live birth rates in women with a predicted poor ovarian response, apparent from a low antral follicle count (AFC), scheduled for IVF or ICSI'SUMMARY ANSWERIn women with a predicted poor ovarian response (AFC < 11) undergoing IVF/ICSI, an increased FSH dose (225/450 IU/day) does not improve cumulative live birth rates as compared to a standard dose (150 IU/day).WHAT IS KNOWN ALREADYIn women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can predict ovarian response to stimulation. The FSH starting dose is often adjusted based on the ORT from the belief that it will improve live birth rates. However, the existing RCTs on this topic, most of which show no benefit, are underpowered.STUDY DESIGN, SIZE, DURATIONBetween May 2011 and May 2014, we performed an open-label multicentre RCT in women with an AFC < 11 (Dutch Trial Register NTR2657). The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. We needed 300 women to assess whether an increased dose strategy would increase the cumulative live birth rate from 25 to 40% (two-sided alpha-error 0.05, power 80%).PARTICIPANTS/MATERIALS, SETTING, METHODSWomen with an AFC ≤ 7 were randomized to an FSH dose of 450 IU/day or 150 IU/day, and women with an AFC 8–10 were randomized to 225 IU or 150 IU/day. In the standard group, dose adjustment was allowed in subsequent cycles based on pre-specified criteria. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective.MAIN RESULTS AND THE ROLE OF CHANCEIn total, 511 women were randomized, 234 with an AFC ≤ 7 and 277 with an AFC 8–10. The cumulative live birth rate for increased versus standard dosing was 42.4% (106/250) versus 44.8% (117/261), respectively [relative risk (RR): 0.95 (95%CI, 0.78–1.15), P = 0.58]. As an increased dose strategy was more expensive [delta costs/woman: €1099 (95%CI, 562–1591)], standard FSH dosing was the dominant strategy in our economic analysis.LIMITATIONS, REASONS FOR CAUTIONDespite our training programme, the AFC might have suffered from inter-observer variation. As this open study permitted small dose adjustments between cycles, potential selective cancelling of cycles in women treated with 150 IU could have influenced the cumulative results. However, since first cycle live birth rates point in the same direction we consider it unlikely that the open design masked a potential benefit for the individualized strategy.WIDER IMPLICATIONS OF THE FINDINGSSince an increased dose in women scheduled for IVF/ICSI with a predicted poor response (AFC < 11) does not improve live birth rates and is more expensive, we recommend using a standard dose of 150 IU/day in these women.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). T.C.T., H.L.T. and S.C.O. received an unrestricted personal grant from Merck BV. H.R.V. receives monetary compensation as a member on an external advisory board for Ferring pharmaceutical BV. B.W.J.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare.TRIAL REGISTRATION NUMBERRegistered at the ICMJE-recognized Dutch Trial Registry ( Registration number NTR2657.TRIAL REGISTRATION DATE20 December 2010.DATE OF FIRST PATIENT’S ENROLMENT12 May 2011.
      PubDate: 2017-11-07
  • Individualized versus standard FSH dosing in women starting IVF/ICSI: an
           RCT. Part 2: The predicted hyper responder
    • Authors: Oudshoorn S; van Tilborg T, Eijkemans M, et al.
      Abstract: STUDY QUESTIONDoes a reduced FSH dose in women with a predicted hyper response, apparent from a high antral follicle count (AFC), who are scheduled for IVF/ICSI lead to a different outcome with respect to cumulative live birth rate and safety'SUMMARY ANSWERAlthough in women with a predicted hyper response (AFC > 15) undergoing IVF/ICSI a reduced FSH dose (100 IU per day) results in similar cumulative live birth rates and a lower occurrence of any grade of ovarian hyperstimulation syndrome (OHSS) as compared to a standard dose (150 IU/day), a higher first cycle cancellation rate and similar severe OHSS rate were observed.WHAT IS KNOWN ALREADYExcessive ovarian response to controlled ovarian stimulation (COS) for IVF/ICSI may result in increased rates of cycle cancellation, the occurrence of OHSS and suboptimal live birth rates. In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can be used to predict response to COS. No consensus has been reached on whether ORT-based FSH dosing improves effectiveness and safety in women with a predicted hyper response.STUDY DESIGN SIZE, DURATIONBetween May 2011 and May 2014, we performed an open-label, multicentre RCT in women with regular menstrual cycles and an AFC > 15. Women with polycystic ovary syndrome (Rotterdam criteria) were excluded. The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. Secondary outcomes included the occurrence of OHSS and cost-effectiveness. Since this RCT was embedded in a cohort study assessing over 1500 women, we expected to randomize 300 predicted hyper responders.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen with an AFC > 15 were randomized to an FSH dose of 100 IU or 150 IU/day. In both groups, dose adjustment was allowed in subsequent cycles (maximum 25 IU in the reduced and 50 IU in the standard group) based on pre-specified criteria. Both effectiveness and cost-effectiveness were evaluated from an intention-to-treat perspective.MAIN RESULTS AND THE ROLE OF CHANCEWe randomized 255 women to a daily FSH dose of 100 IU and 266 women to a daily FSH dose of 150 IU. The cumulative live birth rate was 66.3% (169/255) in the reduced versus 69.5% (185/266) in the standard group (relative risk (RR) 0.95 [95%CI, 0.85–1.07], P = 0.423). The occurrence of any grade of OHSS was lower after a lower FSH dose (5.2% versus 11.8%, RR 0.44 [95%CI, 0.28–0.71], P = 0.001), but the occurrence of severe OHSS did not differ (1.3% versus 1.1%, RR 1.25 [95%CI, 0.38–4.07], P = 0.728). As dose reduction was not less expensive (€4.622 versus €4.714, delta costs/woman €92 [95%CI, −479–325]), there was no dominant strategy in the economic analysis.LIMITATIONS, REASONS FOR CAUTIONDespite our training programme, the AFC might have suffered from inter-observer variation. Although strict cancellation criteria were provided, selective cancelling in the reduced dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as first cycle live birth rates did not differ from the cumulative results, the open design probably did not mask a potential benefit for the reduced dosing group. As this RCT was embedded in a larger cohort study, the power in this study was unavoidably lower than it should be. Participants had a relatively low BMI from an international perspective, which may limit generalization of the findings.WIDER IMPLICATIONS OF THE FINDINGSIn women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose did reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS. Future research into ORT-based dosing in women with a predicted hyper response should compare various safety management strategies and should be powered on a clinically relevant safety outcome while assessing non-inferiority towards live birth rates.STUDY FUNDING/COMPETING INTEREST(S)This trial was funded by The Netherlands Organization for Health Research and Development (ZonMW, Project Number 171102020).SCO, TCvT and HLT received an unrestricted research grant from Merck Serono (the Netherlands). CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV and Merck Serono for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare.TRIAL REGISTRATION NUMBERRegistered at the ICMJE-recognized Dutch Trial Registry ( Registration number: NTR2657.TRIAL REGISTRATION DATE20 December 2010.DATE OF FIRST PATIENT’S ENROLMENT12 May 2011.
      PubDate: 2017-11-07
  • Malignant testicular germ cell tumors in postpubertal individuals with
           androgen insensitivity: prevalence, pathology and relevance of single
           nucleotide polymorphism-based susceptibility profiling
    • Authors: Cools M; Wolffenbuttel K, Hersmus R, et al.
      Abstract: STUDY QUESTIONWhat is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT'SUMMARY ANSWERNo GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333).WHAT IS KNOWN ALREADYMany adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown.STUDY DESIGN, SIZE, DURATIONThis multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology.PARTICIPANTS/MATERIALS, SETTING, METHODSMaterial from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14–54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies.MAIN RESULTS AND ROLE OF CHANCEThe earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs.LARGE SCALE DATAN/A.LIMITATIONS REASONS FOR CAUTIONA limited number of cases were included.WIDER IMPLICATIONS OF THE FINDINGSOur data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.
      PubDate: 2017-11-07
  • MAEL promoter hypermethylation is associated with de-repression of LINE-1
           in human hypospermatogenesis
    • Authors: Cheng Y; Wee S, Lin T, et al.
      Abstract: STUDY QUESTIONDoes the hypermethylation of the maelstrom spermatogenic transposon silencer (MAEL) promoter and subsequent de-repression of transposable elements represent one of the causes of spermatogenic failure in infertile men'SUMMARY ANSWERExperimental hypermethylation of a specific region (−131 to +177) of the MAEL promoter leads to decreased expression of MAEL with increased expression of the transposable element LINE-1 (L1) and in infertile men methylation of the MAEL promoter is associated with the severity of spermatogenic failure.WHAT IS KNOWN ALREADYMAEL induces transposon repression in the male germline and is required for mammalian meiotic progression and post-meiotic spermiogenesis. Patients with non-obstructive azoospermia (NOA), defined as no sperm in the ejaculate due to spermatogenic failure, and histopathologically proven hypospermatogenesis (HS) is not uncommon and its etiology is largely unknown.STUDY DESIGN, SIZE, DURATIONLuciferase reporter assay and a targeted DNA methylation model were used to explore the effects of hypermethylation of MAEL promoter on gene expression. Germ cell-enriched testicular cells from infertile patients were used to determine the methylation levels of MAEL and expressions of MAEL and L1.PARTICIPANTS/MATERIALS, SETTING, METHODSTwenty-six patients with histopathologically proven NOA and HS and 12 patients with obstructive azoospermia and normal spermatogenesis (NS) were enrolled in this study. Demographic and clinical information were obtained. The severity of HS was determined by a spermatogenic scoring system. The methylation levels of 26 CpGs in the MAEL promoter was measured, and quantitative real-time RT-PCR was used to determine the expressional levels of MAEL and L1.MAIN RESULTS AND THE ROLE OF CHANCETargeted DNA methylation of MAEL promoter suppressed MAEL expression and de-repressed L1 activity in vitro. Patients with HS had significantly higher mean methylation levels of 26 consecutive CpGs in the MAEL promoter, compared to patients with NS. The MAEL methylation levels were negatively correlated with MAEL transcript levels and higher methylation level of MAEL was associated with severe spermatogenic defect. L1 transcript level was significantly higher in patients with HS. No differences in age, frequency of testicular insults and genetic anomalies was noted between patients with high or low MAEL methylation levels.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONBecause of the difficulty in the use of human germ cells for study, the in vitro targeted DNA methylation model was performed by using human NCI-H358 cells to explore the effects of MAEL methylation on transposable elements activity. Because the germ cell-enriched testicular cells isolated from a testicular sample were relatively few, the purity of cell populations was not determined.WIDER IMPLICATIONS OF THE FINDINGSMeasurement of the methylation level of MAEL gene may be feasible to predict the severity of spermatogenic failure or the outcome of testicular sperm retrieval.STUDY FUNDING/COMPETING INTERESTSThis work was supported through grants from the Ministry of Science and Technology of Taiwan (100-2314-B-006-017) and National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH 20120266). The authors declare no conflicts of interest.
      PubDate: 2017-10-31
  • Alterations in the sperm histone-retained epigenome are associated with
           unexplained male factor infertility and poor blastocyst development in
           donor oocyte IVF cycles
    • Authors: Denomme M; McCallie B, Parks J, et al.
      Abstract: STUDY QUESTIONIs there a distinct sperm histone-retained epigenetic signature in unexplained male factor infertility patients resulting in compromised blastocyst development'SUMMARY ANSWERUsing only donor oocyte IVF cycles, sperm DNA methylation patterns and miRNA profiles were significantly altered in normozoospermic patients resulting in poor blastocyst development, reflecting a subset of unexplained male factor infertility.WHAT IS KNOWN ALREADYAberrant sperm DNA methylation has been associated with known male factor infertility, particularly noted in oligozoospermic patients. Unexplained male factor infertility remains a significant proportion of in vitro fertilization failures having unknown underlying physiology.STUDY DESIGN, SIZE, DURATIONSperm samples (n = 40) and blastocysts (n = 48) were obtained during fertile donor oocyte IVF cycles with normozoospermic parameters, thereby excluding known female and male infertility factors. Samples were divided into two groups based on blastocyst development (Good Group = ≥20% embryos with D5 grade ‘AA’ blastocysts, and ≥60% embryos of transferable quality on D5 and D6; Poor Group = ≤10% embryos with D5 grade ‘AA’ blastocysts, and ≤40% embryos of transferable quality on D5 and D6).PARTICIPANTS/MATERIALS, SETTING, METHODSSamples were obtained from patients undergoing IVF treatments with informed consent and institutional review board approval. The Infinium HumanMethylation450 BeadChip microarray was used to identify histone-retained CpG island genes and genomic regions showing differences in sperm DNA methylation between the Good Group and the Poor Group. Pathway and gene network analysis for the significantly altered genes was performed, and targeted DNA methylation validation was completed for 23 genes and two imprinting control regions. Sperm miRNA profiles were assessed using the TaqMan® Human MicroRNA Array Card, with corresponding blastocyst mRNA gene expression examined by qRT-PCR.MAIN RESULTS AND THE ROLE OF CHANCEOur study is the first to investigate unexplained male factor infertility while significantly eliminating confounding female factors from our sample population by using only young fertile donor oocytes. We identified 1634 CpG sites located at retained histone CpG island regions that had significant sperm DNA methylation differentials between the two embryogenesis groups (P < 0.05). A largely hypermethylated profile was evident in the Good Group, with a small but distinct and statistically significant shift (P < 0.05) observed in the Poor Group. Genes involved in embryonic development were highly represented among histone-retained CpG sites with decreased methylation in the Poor Group (P < 0.05). Ten significantly altered sperm miRNAs (P < 0.05), correlated with altered target gene mRNA expression in the blastocysts from the Poor Group (P < 0.05). Taken together, significantly impacted sperm miRNA and target transcript levels in blastocysts from the Poor Group may contribute alongside aberrant sperm DNA methylation to the compromised blastocyst development observed.LIMITATIONS, REASONS FOR CAUTIONOur examination of CpG island regions restricted to retained histones represents only a small part of the sperm epigenome. The results observed are descriptive and further studies are needed to elucidate the functional effects of differential sperm DNA methylation on unexplained male factor infertility and blastocyst development.WIDER IMPLICATIONS OF THE FINDINGSSlight epigenetic changes in sperm may have a cumulative effect on fertility and embryonic developmental competence. Knowledge of sperm epigenetics and inheritance has important implications for future generations, while providing evidence for potential causes of unexplained male factor infertility.STUDY FUNDING/COMPETING INTEREST(S)No external funding was used for this study. None of the authors have any competing interest.
      PubDate: 2017-10-26
  • Cumulus cells surrounding oocytes with high developmental competence
           exhibit down-regulation of phosphoinositol 1,3 kinase/protein kinase B
           (PI3K/AKT) signalling genes involved in proliferation and survival
    • Authors: Artini P; Tatone C, Sperduti S, et al.
      Abstract: STUDY QUESTIONIs the phosphoinositol 1,3-kinase/protein kinase B (PI3K/AKT) pathway expression profile in cumulus cells (CCs) a potential marker of oocyte competence and predictive of pregnancy outcome'SUMMARY ANSWEREleven genes (AKT1, ARHGEF7, BCL2L1, CCND1, E2F1, HRAS, KCNH2, PIK3C2A, SHC1, SOS1 and SPP1) in the PI3K/AKT pathway were significantly down-regulated in CCs from oocytes that went on to produce a pregnancy compared to CCs associated with a negative outcome.WHAT IS KNOWN ALREADYThe PI3K/AKT pathway plays a pivotal role in the interdependence and continuous feedback between the oocyte and CCs.STUDY DESIGN SIZE, DURATIONThe expression analysis of 92 transcripts in the PI3K/AKT pathway in CCs from patients with negative or positive pregnancy outcome, after single embryo transfer, was performed. Mouse CCs target gene expression was conducted to associate the expression profile of PI3K/AKT pathway to oocyte developmental profile.PARTICIPANTS/MATERIALS, SETTING, METHODSFifty-five good prognosis IVF patients who had been referred to IVF or intracytoplasmic sperm injection treatment for male-factor infertility or tubal disease were enroled. CCs from single cumulus-oocyte complexes (COCs) from 16 patients who underwent a single embryo transfer were analyzed. Twenty-five CD-1 mice were used to assess gene expression in CCs associated with oocytes with different competence in relation to hCG priming. A total 220 human COCs were collected. The RNA extracted from CCs of 16 selected patients was used to analyze PI3K/AKT pathway gene expression employing a 96-well custom TaqMan Array. Expression data of CCs associated to positive IVF outcome were compared to data from negative outcome samples. Mice were sacrificed after 9, 12, 15, 21 and 24 h post-hCG administration to obtain CCs from MII oocytes with different developmental competence. Akt1, Bcl2l2 and Shc1 expression were tested in the collected mouse CCs. In addition, the expression of upstream regulator ESR1, the gene encoding for the oestrogen receptor ERβ, and the downstream effectors of the pathway FOXO1, FOXO3 and FOXO4 was evaluated in human and mouse samples.MAIN RESULTS AND THE ROLE OF CHANCETranscripts involved in the PI3K Signaling Pathway were selectively modulated according to the IVF/ICSI outcome of the oocyte. Eleven transcripts in this pathway were significantly down-regulated in all samples of CCs from oocytes with positive when compared those with a negative outcome. These outcomes were confirmed in mouse CCs associated with oocytes at different maturation stages. Expression data revealed that the down-regulation of ESR1 could be related to oocyte competence and is likely to be the driver of expression changes highlighted in the PI3K/AKT pathway.LIMITATIONS REASONS FOR CAUTIONSmall sample size and retrospective design.WIDER IMPLICATIONS OF THE FINDINGSThe CCs expression profile of PI3K/AKT signaling genes, disclosed a specific CCs gene signature related to oocyte competence. It could be speculated that CCs associated with competent oocytes have completed their role in sustaining oocyte development and are influencing their fate in response to metabolic and hormonal changes by de-activating anti-apoptotic signals.STUDY FUNDING/COMPETING INTEREST(S)Supported by Merck Serono an affiliate of Merck KGaA, Darmstadt, Germany (research grant for the laboratory session; Merck KGaA reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors). The authors declare no conflict of interest.
      PubDate: 2017-10-26
  • Cardiovascular health of 9-year-old IVF offspring: no association with
           ovarian hyperstimulation and the in vitro procedure
    • Authors: Kuiper D; Hoek A, la Bastide-van Gemert S, et al.
      Abstract: STUDY QUESTIONAre the in vitro procedure, ovarian hyperstimulation or a combination of these two associated with blood pressure (BP) of 9-year-old IVF children born to subfertile couples'SUMMARY ANSWEROur study demonstrates that ovarian hyperstimulation and the in vitro procedure are not associated with BP values in 9-year-old children born to subfertile couples.WHAT IS KNOWN ALREADYPossible long-term effects of IVF on child health and development have been studied relatively little. This is surprising, as it is known that environmental conditions may influence embryonic and foetal development which may result in health related problems in later life. Some studies suggested that IVF is associated with higher BP at pre-school age. Yet, it is unclear whether this may be also true for older children and if so, which component of IVF, i.e. the ovarian hyperstimulation, the embryo culture or a combination of these, attributes to this potentially less favourable BP.STUDY DESIGN, SIZE, DURATIONThe Groningen Assisted Reproductive Technology cohort-study is a prospective assessor-blinded study of children followed from before birth onwards. In total, 170 children were assessed at the age of 9 years. The attrition rate up until the 9-year-old assessment was 21%.PARTICIPANTS/MATERIALS, SETTING, METHODSWe evaluated cardiovascular health, focusing on BP (in mmHg and the internationally recognized percentiles of the US National High BP Education Program), heart rate and anthropometrics of 57 children born following controlled ovarian hyperstimulation-IVF/ICSI (COH-IVF/ICSI); 47 children born after modified natural cycle-IVF/ICSI (MNC-IVF/ICSI); and 66 children who were conceived naturally by subfertile couples (Sub-NC). Cardiovascular parameters were measured multiple times on one day. In addition, anthropometric data, including BMI and skinfold thickness, were collected.MAIN RESULTS AND THE ROLE OF CHANCESystolic BP in mmHg did not differ between the COH-IVF/ICSI (mean 106.9, SD 6.7), MNC-IVF/ICSI (mean 104.8, SD 5.9) and Sub-NC (mean 106.3, SD 5.3) groups. In addition, systolic BP percentiles did not differ between the groups: COH-IVF/ICSI (mean 62.4, SD 20.2); MNC-IVF/ICSI (mean 56.3, SD 19.3); and Sub-NC (mean 62.3, SD17.8). Also, after adjustment for confounders BP in the three groups was similar. Heart rate and anthropometric values in the three groups did not differ. For instance, BMI values in the COH-IVF/ICSI-children were 16.3 (median value, range 13.0–24.7), in MNC-IVF/ICSI-children 16.1 (range 12.7–22.5) and in Sub-NC children 16.3 (range 12.7–24.0).LIMITATIONS, REASONS FOR CAUTIONThe size of our study groups does not allow for pertinent conclusions on the effect of ovarian hyperstimulation and the in vitro procedure. The lack of a fertile control group may be regarded as another limitation.WIDER IMPLICATIONS OF THE FINDINGSOur study suggests that ovarian hyperstimulation and in vitro procedures are not associated with cardiovascular health in 9-year-old. Yet, BP percentiles of the three groups were higher than the expected 50th percentile. This might indicate that children of subfertile couples have a higher BP than naturally conceived children.STUDY FUNDING/COMPETING INTEREST(S)The study was financially supported by the University Medical Center Groningen (UMCG), the two graduate schools of the UMCG, BCN, SHARE and the Cornelia Stichting. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.
      PubDate: 2017-10-26
  • Allowable warm ischemic time and morphological and biochemical changes in
           uterine ischemia/reperfusion injury in cynomolgus macaque: a basic study
           for uterus transplantation
    • Authors: Kisu I; Umene K, Adachi M, et al.
      PubDate: 2017-10-25
  • Direct actions of androgen, estrogen and anti-Müllerian hormone on
           primate secondary follicle development in the absence of FSH in vitro
    • Authors: Baba T; Ting A, Tkachenko O, et al.
      Abstract: STUDY QUESTIONWhat are effects of androgen, estrogen and anti-Müllerian hormone (AMH), independent of FSH action, on the development and function of primate follicles from the preantral to small antral stage in vitro'SUMMARY ANSWERAndrogen and estrogen, but not AMH, promote follicle survival and growth in vitro, in the absence of FSH. However, their growth-promoting effects are limited to the preantral to early antral stage.WHAT IS KNOWN ALREADYFSH supports primate preantral follicle development in vitro. Androgen and estrogen augment follicle survival and growth in the presence of FSH during culture.STUDY DESIGN SIZE, DURATIONNonhuman primate model; randomized, control versus treatment groups. Rhesus macaque (n = 6) secondary follicles (n = 24 per animal per treatment group) were cultured for 5 weeks.PARTICIPANTS/MATERIALS, SETTING, METHODSFollicles were encapsulated in 0.25% (w/v) alginate and cultured individually in modified alpha minimum essential media with (i) FSH (1 ng/ml; control), (ii) no FSH, (iii) no FSH + estradiol (E2; 100 pg/ml)/dihydrotestosterone (DHT; 50 ng/ml) and (iv) no FSH + AMH (50 ng/ml). In a second experiment, follicles were cultured with (i) FSH (1 ng/ml), (ii) no FSH, (iii) no FSH + E2 (1 ng/ml), (iv) no FSH + DHT (50 ng/ml) and (v) no FSH + E2/DHT. Follicle survival, antrum formation and growth pattern were evaluated. Progesterone (P4), E2 and AMH concentrations in culture media were measured.MAIN RESULTS AND THE ROLE OF CHANCEIn the first experiment, FSH deprivation significantly decreased (P < 0.05) follicle survival rates in the no FSH group (16 ± 5%), compared to CTRL (66 ± 9%). E2/DHT (49 ± 5%), but not AMH (27 ± 8%), restored follicle survival rate to the CTRL level. Similarly, antrum formation rates were higher (P < 0.05) in CTRL (56 ± 6%) and E2/DHT groups (54 ± 14%), compared to no FSH (0 ± 0%) and AMH (11 ± 11%) groups. However, follicle growth rate after antrum formation and follicle diameter at week 5 was reduced (P < 0.05) in the E2/DHT group (405 ± 25 μm), compared to CTRL (522 ± 29 μm). Indeed, the proportion of fast-grow follicles at week 5 was higher in CTRL (29% ± 5), compared to E2/DHT group (10 ± 3%). No fast-grow follicles were observed in no FSH and AMH groups. AMH levels at week 3 remained similar in all groups. However, media concentrations of P4 and E2 at week 5 were lower (P < 0.05, undetectable) in no FSH, E2/DHT and AMH groups, compared to CTRL (P4 = 93 ± 10 ng/ml; E2 = 4 ± 1 ng/ml). In the second experiment, FSH depletion diminished follicle survival rate (66 ± 8% in control versus 45 ± 9% in no FSH, P = 0.034). E2 plus DHT (31.5 ± 11%) or DHT alone (69 ± 9%) restored follicle survival rate to the control (FSH) level as expected. Also, E2 plus DHT or DHT alone improved antrum formation rate. However, in the absence of FSH, E2 plus DHT or DHT alone did not support growth, in terms of follicle diameter, or steroid (P4 or E2) production after the antral stage.LIMITATIONS REASONS FOR CAUTIONThis study is limited to in vitro effects of E2, DHT and AMH during the interval from the secondary to small antral stage of macaque follicular development. In addition, the primate follicle pool is heterogeneous and differs between animals; therefore, even though only secondary follicles were selected, follicle growth and developmental outcomes might differ from one animal to another.WIDER IMPLICATIONS OF THE FINDINGSThis study provides novel information on the possible actions of estrogen and androgen during early follicular development in primates. Our results suggest that sequential exposure of preantral follicles to local factors, e.g. E2 and DHT, followed by gonadotropin once the follicle reaches the antral stage, may better mimic primate folliculogenesis in vivo.STUDY FUNDING/COMPETING INTEREST(S)Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Center for Translational Research on Reproduction and Infertility 5P50HD071836, and the NIH Primate Centers Program 8P510D011092. There are no conflicts of interest.
      PubDate: 2017-10-25
  • Adult adiposity and risk of early menopause
    • Authors: Szegda K; Whitcomb B, Purdue-Smithe A, et al.
      Abstract: STUDY QUESTIONIs adult adiposity associated with early menopause'SUMMARY ANSWEROverall and abdominal adiposity were non-linearly associated with odds for early natural menopause with elevated odds observed among women who were underweight in early or mid-adulthood compared to lean-normal weight women.WHAT IS KNOWN ALREADYHigh and low adiposity have been associated with reproductive function and may potentially impact timing of menopause. It is unclear whether various aspects of adiposity are associated with risk of early menopause.STUDY DESIGN, SIZE, DURATIONProspective cohort study that examined data from 78 759 premenopausal women from the Nurses’ Health Study II who were followed from 1989 to 2011 for incidence of early natural menopause.PARTICIPANTS/MATERIALS, SETTING, METHODSParticipants were aged 25–42 years and premenopausal at baseline in 1989, when information on menopausal status, height and weight was reported via questionnaire. Information on menopausal status, type of menopause (natural, surgical, radiation/chemotherapy), hormone therapy use and weight was updated every two years along with information on smoking, physical activity and other behavioral and health-related factors. Multivariable logistic regression was used to estimate odds ratios for early menopause, defined as natural menopause before age 45 years, by aspects of adiposity.MAIN RESULTS AND THE ROLE OF CHANCEEarly natural menopause was reported by 2804 participants. Body mass index (BMI) was non-linearly associated with risk for early menopause. Compared to women with BMI = 18.5–22.4 kg/m2, those with BMI < 18.5 kg/m2 had a significant 30% higher odds of early menopause (95% confidence interval (CI) = 1.08, 1.57), while women with BMIs between 25.0–29.9 kg/m2 had significant 21–30% lower odds. Odds were not higher in women with BMI ≥ 35.0 kg/m2 in fully adjusted analysis. Non-linear associations with higher odds in underweight women were also observed for age 18 and age 35 BMI, though lower odds for overweight women was only observed for age 35 BMI. Odds were highest among women with age 18 BMI < 18.5 kg/m2 reporting severe weight cycling.LIMITATIONS, REASONS FOR CAUTIONThough weight and early menopause status were self-reported, validation studies conducted among Nurses’ Health Study participants suggest that self-reported weight is highly correlated with directly measured weight, and prospective self-reported menopausal status is highly reproducible. It is possible that underweight women may have been misclassified with an earlier age at menopause if being underweight led to amenorrhea.WIDER IMPLICATIONS OF THE FINDINGSIn one of the few studies to prospectively examine a variety of adiposity measures and risk for early menopause, our findings that women who were underweight in early or mid-adulthood had elevated risk for early menopause can assist in efforts to better understand the etiology of early menopause. Additional prospective research is needed to understand how low adiposity may physiologically impact timing of menopause.STUDY FUNDING/COMPETING INTEREST(S)This study was conducted with funding from NIH UM1CA176726 and R01HD078517. The authors declare no conflicts of interest.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: 2017-10-25
  • Urinary concentrations of 3-(diethylcarbamoyl)benzoic acid (DCBA), a major
           metabolite of N,N-diethyl-m-toluamide (DEET) and semen parameters among
           men attending a fertility center
    • Authors: Segal T; Mínguez-Alarcón L, Chiu Y, et al.
      Abstract: STUDY QUESTIONAre specific gravity (SG)-adjusted urinary concentrations of 3-(diethylcarbamoyl)benzoic acid (DCBA) associated with semen parameters among men attending an academic fertility center'SUMMARY ANSWEROur study did not demonstrate any association between SG-adjusted urinary DCBA concentrations and semen parameters among men attending an academic fertility center.WHAT IS KNOWN ALREADYN,N-Diethyl-m-toluamide (DEET) is the most common active ingredient in consumer insect repellents. The recent rise in public health concerns regarding mosquito-borne diseases such as Zika, have led to an increased use of DEET insect repellents, especially among couples planning pregnancy. Animal studies have observed reproductive toxicity from DEET exposure. However, the reproductive health effects of DEET and its metabolites on human reproduction are unknown.STUDY DESIGN, SIZE, DURATIONBetween 2007 and 2015, 90 men participating in a prospective cohort study at the Massachusetts General Hospital Fertility Center provided 171 urine samples and 250 semen samples for analysis.PARTICIPANTS/MATERIALS, SETTING, METHODSThe urinary concentrations of DEET, N,N-diethyl-3-hydroxymethylbenzamide (DHMB) and DCBA were quantified by isotope-dilution tandem mass spectrometry and adjusted by SG. We used linear mixed models to evaluate the association between tertiles of SG-adjusted urinary DCBA concentrations and semen parameters (semen volume, sperm concentration, total sperm count, progressive motility, total progressive motility count, normal morphology and total normal morphology count), adjusting for covariates. DEET and DHMB were not considered for analysis because of the low percentage of detectable concentrations (<7%). Effect modification by BMI and smoking status was explored.MAIN RESULTS AND THE ROLE OF CHANCEParticipants had a median age of 36 years and BMI of 27 kg/m2, and 68% had never smoked. The SG-adjusted geometric mean DCBA urinary concentration was 2.20 μg/l, with 85% detection frequency. The majority of semen parameters fell within the normal range with the exception of progressive motility, where 64% of the men had values below the WHO 2010 lower reference limits. SG-adjusted urinary DCBA concentrations were not associated with semen parameters in unadjusted or adjusted models. Men in the highest tertile of SG-adjusted urinary DCBA concentrations had comparable semen parameters to men in the lowest tertile (2.59 vs. 2.88 ml for semen volume, 47.9 vs. 45.8 million/ml for sperm concentration, 116 vs. 118 million for total sperm count, 25 vs. 24% for progressive sperm motility, and 6.1 vs. 5.8% for morphologically normal sperm). In addition, BMI and smoking status did not modify the associations.LIMITATIONS REASONS FOR CAUTIONWe had a relatively small sample size with similar socioeconomic backgrounds and with overall relatively low urinary concentrations of DEET biomarkers. However, our sample size was enough to detect moderate differences with at least 80% statistical power, between the first and third tertiles of urinary DCBA concentrations. Limitations also include possible misclassification of DCBA exposure and difficulties in extrapolating the findings to the general population.WIDER IMPLICATIONS OF THE FINDINGSOur study found no associations between urinary concentrations of DCBA, a major metabolite of the insect repellent DEET, and semen parameters in men presenting for infertility treatment. While these results are reassuring, further studies including larger sample sizes and higher exposures are warranted.STUDY FUNDING/COMPETING INTEREST(S)The project was financed by the National Institute of Health grants R01ES022955 and R01ES009718 and by grant P30ES000002 from the National Institute of Environmental Health Sciences (NIEHS). None of the authors has any conflicts of interest to declare. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.TRIAL REGISTRATION NUMBERN/A.
      PubDate: 2017-10-25
  • Poor recovery of households from out-of-pocket payment for assisted
           reproductive technology
    • Authors: Dyer S; Vinoos L, Ataguba J.
      Abstract: STUDY QUESTIONHow do households recover financially from direct out-of-pocket payment for government subsidized ART'SUMMARY ANSWERAfter a mean of 3.8 years, there was poor recovery from initiated financial coping strategies with the poorest households being disproportionatley affected.WHAT IS KNOWN ALREADYOut-of-pocket payment for health services can create financial burdens for households and inequities in access to care. A previous study conducted at a public-academic institution in South Africa documented that patient co-payment for one cycle of ART resulted in catastrophic expenditure for one in five households, and more frequently among the poorest, requiring diverse financial coping strategies to offset costs.STUDY DESIGN, SIZE, DURATIONAn observational follow-up study was conducted ~4 years later to assess financial recovery among the 135 couples who had participated in this previous study. Data were collected over 12 months from 73 informants.PARTICIPANTS/MATERIALS, SETTING, METHODThe study was conducted at a level three referral hospital in the public-academic health sector of South Africa. At this institution ART is subsidized but requires patient co-payments. A purpose-built questionnaire capturing socio-economic information and recovery from financial coping strategies which had been activated was administered to all informants. Financial recovery was defined as the resolution of strategies initiated for the specific purpose of covering the original ART cycle. Results were analysed by strategy and household with the latter including analysis by tertiles based on socio-economic status at the time of the original expenditure. In addition to descriptive statistics, the Pearson Chi squared test was used to determine differences between socioeconomic tertiles and associations between recovery and other variables.MAIN RESULTS AND THE ROLE OF CHANCEThe participation rate in this follow-up study was 54.1% with equal representation from the three socio-economic tertiles. The average duration of follow-up was 46.1 months (±9.78 SD) and respondents’ mean age was 42 years (range 31–52). The recovery rate was below 50% for four of five strategies evaluated: 23.1% of households had re-purchased a sold asset; 23.5% had normalized a previous reduction in household spending, 33.8% had regained their savings, and 48.7% were no longer bolstering income through additional work. Two-thirds of households (60.0%) had repaid all loans and debts. The poorest households showed lower rates of recovery when compared to households in the richest tertile. Complete recovery from all strategies initiated was reported by only 10 households (13.7%): 1 of 19 in the lowest tertile, 3 of 30 in the middle and by 6 of 24 households in the richest tertile (P > 0.05). No association was found between the degree of financial recovery and additional cost burdens incurred, including related to babies born; or between the degree of recovery and ongoing pursuit of ART.LIMITATIONS, REASONS FOR CAUTIONThe sample size was limited. The participation rate was just over 50%. Results were dependent on participants’ narrative and recall.WIDER IMPLICATIONS OF THE FINDINGSThe willingness of patients to pay for ART does not necessarily imply the ability to pay. As a result, the lack of comprehensive third-party funding for ART can create immediate and long-term financial hardship which is more pronounced among poorer households. While more data on the impact of out-of-pocket payment for ART are needed to illustrate the problem in other low resource settings, the results from South Africa provide useful information for similar developing countries. The current absence of more extensive data should therefore not be a barrier to the promotion of financial risk protection for infertile couples, especially the poorest, in need of ART.STUDY FUNDING/COMPETING INTEREST(S)The study was supported by a Masters Student Grant from the Faculty of Health Sciences, University of Cape Town. The authors had no competing interests.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: 2017-10-21
  • Survey of Reproductive Experiences and Outcomes of Cancer Survivors Who
           Stored Reproductive Material Before Treatment
    • Authors: Hammarberg K; Kirkman M, Stern C, et al.
      Abstract: STUDY QUESTIONWhat are the reproductive experiences and outcomes of people who store reproductive material before cancer treatment'SUMMARY ANSWEROf respondents who had tried to achieve pregnancy since completing cancer treatment almost all had succeeded, in most cases through natural conception.WHAT IS KNOWN ALREADYPeople of reproductive age who are diagnosed with cancer can cryopreserve reproductive material to guard against the adverse effects on fertility of gonadotoxic treatment. Little is known about the reproductive outcomes of people who undergo fertility preservation before cancer treatment.STUDY DESIGN, SIZE, DURATIONCross-sectional survey.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen and men who had stored reproductive material before cancer treatment at two private and one public fertility clinics up to June 2014 and were at least 18 years old at the time were identified from medical records and invited to complete an anonymous questionnaire about their reproductive experiences.MAIN RESULTS AND THE ROLE OF CHANCEOf the 870 potential respondents 302 (171 female and 131 male) returned completed questionnaires yielding a response rate of 34.5% (39.5% and 29.7% for female and male respondents, respectively). Current age was similar for women and men (37.2 years) but men had been diagnosed with cancer significantly earlier in life than women (28.2 versus 30.3 years, P = 0.03). Almost two-thirds of respondents wished to have a child or another child in the future, some of whom knew that they were unable to. One in ten respondents was a parent before the cancer diagnosis and around one-third had had a child since diagnosis or was pregnant (or a partner in pregnancy) at the time of the survey. Of those who had tried to conceive since completing cancer treatment (N = 119) 84% (79% of women and 90% of men) had had a child or were pregnant (or a partner in pregnancy). Most of the pregnancies since the diagnosis of cancer occurred after natural conception (58/100, 58%). Of the 22 women (13% of all women) and 35 men (27% of all men) who had used their stored reproductive material four women (18%) and 28 men (80%) had had a child or were pregnant or a partner in pregnancy at the time of completing the survey. The most commonly stated reason for not using the stored material was not being ready to try for a baby.LIMITATIONS, REASON FOR CAUTIONThe relatively low response rate, particularly among men, means that participation bias may have influenced the findings. As type of cancer was self-reported and we did not ask questions about respondents’ cancer treatments, it is not possible to link reproductive outcomes to type of cancer or cancer treatment. Also, there is no way of comparing the sample with the populations they were drawn from as data on reproductive outcomes of people who store reproductive material before cancer treatment are not collected routinely. This might have led to over- or underestimates of the reproductive experiences and outcomes reported in this paper.WIDER IMPLICATIONS OF THE FINDINGSThe findings add to the limited evidence about the reproductive outcomes of this growing group of people and can be used to inform the advice given to those contemplating fertility preservation in the context of cancer.STUDY FUNDING/COMPETING INTERESTSThe study was funded by the National Health and Medical Research Council (APP1042347). The authors have no conflicts of interest to declare.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: 2017-10-17
  • Age-related changes in the mitochondria of human mural granulosa cells
    • Authors: Liu Y; Han M, Li X, et al.
      Abstract: STUDY QUESTIONWhat changes in the mitochondria of human mural granulosa cells (mGCs) with maternal aging'SUMMARY ANSWERThe mitochondrial membrane potential (MMP) and the ability of oxidative phosphorylation (OXPHOS) of mGCs declines with reproductive aging, accompanied with more abnormal mitochondria.WHAT IS KNOWN ALREADYMitochondria play an important role in the dialogue between the mGCs and oocytes. However, the underlying mechanism of mitochondrial dysfunction in mGCs in aging is still poorly understood.STUDY DESIGN SIZE, DURATIONIn total, 149 infertile women underwent IVF in the ART Centre of the Chinese PLA General Hospital, China from September 2016 to May 2017. Two age groups were investigated: the young group (<38 years old) and the old group (≥38 years old).PARTICIPANTS/MATERIALS, SETTING, METHODSThe mitochondrial ultrastructure of mGCs was observed by transmission electron microscopy, and real-time quantitative polymerase chain reaction was applied to quantify the mitochondrial DNA (mtDNA) copy number, 4977-bp deleted DNA and mRNA expression of mitochondrial ATP synthases ATP5A1 and ATP5I. MMP was detected by flow cytometry and fluorescence microscopy, respectively. Reactive oxygen species (ROS) was tested by flow cytometry. A luminometer was used to measure the ATP levels and western blot to analyse the OXPHOS complex.MAIN RESULTS AND THE ROLE OF CHANCEIn the young group, mitochondria were mostly round or oval, with a few intact parallel tubular–vesicular cristae and homogenous matrix density, while elongated mitochondria were mainly observed in the old group, which had numerous cristae and more high-density matrix particles. Abnormal mitochondria were more common in aging women (P = 0.012). mtDNA relative copy number was positively correlated with maternal age (r = 0.294, P = 0.009) and we found no one with 4977-bp deleted mitochondria. JC-1 (dye used as an indicator of MMP) ratio in the old group was significantly lower than the young group (3.01 ± 0.21 vs 3.85 ± 0.27, P = 0.033). Intracellular ROS levels between the groups did not differ significantly (P = 0.191). The intracellular ATP level in the young group was 1.75-fold higher than that of the advanced-age group (7.17 ± 1.16 vs 4.15 ± 0.60, P = 0.025). The protein expression of ATP5A1, as one of five proteins of OXPHOS, decreased with aging (P < 0.001). ATP5A1 mRNA expression was negatively correlated with aging (r = −0.341, P = 0.012).LIMITATIONS REASONS FOR CAUTIONThe quantity of mGCs from some individual patient, especially an advanced-age individual, was small, which cannot meet the demands of all the detections.WIDER IMPLICATIONS OF THE FINDINGSmGCs dysfunction with aging is mainly linked to impaired mitochondrial function, especially OXPHOS function. Improving the OXPHOS ability in mGCs should be the focus in resolving infertility among advanced age women and making mGCs the proper mitochondria donor cells in the autologous mitochondria transplantation to oocytes.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the grants of the National High Technology Research and Development Program of China, 863 Program No. SS2015AA020402, and the Key Projects of Military Medical Research, No. BWS11J058. There were no competing interests.
      PubDate: 2017-10-17
  • Pinopode score around the time of implantation is predictive of successful
           implantation following frozen embryo transfer in hormone replacement
    • Authors: Jin X; Zhao L, Luo D, et al.
      Abstract: STUDY QUESTIONIs pinopode measurement of any prognostic value'SUMMARY ANSWERPinopode expression was significantly associated with the occurrence of pregnancy after frozen embryo transfer.WHAT IS KNOWN ALREADYPinopodes are expressed in the endometrium during the implantation period. Pinopode measurement has been proposed as a marker of endometrial receptivity.STUDY DESIGN, SIZE, DURATIONA prospective cohort study was conducted at the Center of Reproductive Medicine, Sir Run Run Shaw Hospital, between 2014 and 2016, recruiting 172 women with infertility and undergoing frozen embryo transfer following IVF treatment. Among 172 participants, 46 women took part in the first study to quantify the daily changing pattern of pinopodes 3–7 days after the initiation of progesterone therapy in the hormone replacement cycles and the remaining 126 women with infertility participated in a study to examine the relationship between pinopode count and pregnancy outcome following frozen embryo transfer in hormone replacement cycles.PARTICIPANTS/MATERIALS, SETTING, METHODSThe mean age of participants was 29 years old. All participants received an artificial hormone replacement protocol capable of supporting successful implantation. Endometrial biopsies from 46 women were obtained 3, 4, 5, 6 and 7 days after the initiation of progesterone therapy (P + 3, n = 6; P + 4, n = 6; P + 5, n = 11; P + 6, n = 13; P + 7, n = 10, respectively). Another 126 endometrial biopsies were obtained precisely 6 days after the initiation of progesterone. Scanning electron microscopy was used to capture the pinopode images, followed by use of the image J program to quantify the count and subtype of the pinopodes.MAIN RESULTS AND THE ROLE OF CHANCEWe found that at least 60 microscopic fields were necessary to achieve a reproducible result. An intra-observer variability study showed good agreement between two measurements regarding the developing pinopode (DP) subtype (r = 0.95) and the fully developed pinopode (FDP) subtype (r = 0.86) but not for the regressing (RP) pinopode subtype (r = 0.39). The proportion of DP/total pinopodes (TP) declined rapidly form day P + 4 to a minimum on day P + 6. The percentage of FDP/TP increased rapidly from day P + 4 to reach a peak on day P + 6. On the other hand, the percentage of RP/TP reached a peak on day P + 7. Participants who conceived had a significantly (P = 0.011) higher percentage of FDP/TP on day P + 6 and significantly (P = 0.005) lower percentage of DP/TP on the same day compared with participants who did not become pregnant. Using a scoring system incorporating the percentages of DP and FDP, it was found that the pregnancy rate and the embryo implantation rate of women with a high pinopode score (82.3%; 63.0%) was significantly (P = 0.001; P = 0.046) higher than that of women with a low pinopode score (53.3%; 46.7%), respectively. There remains a possibility that the observations could have arisen due to chance.LIMITATIONS, REASONS FOR CAUTIONThis study examined pinopode count and subtype in the HRT cycles, and it is uncertain whether the same observations apply to in natural cycles.WIDER IMPLICATIONS OF THE FNDINGSPinopodes have been questioned as a potential marker of endometrial receptivity for many years. Our results suggested that pinopode measurement may be of value in predicting pregnancy.STUDY FUNDING/COMPETING INTEREST(S)The study was supported by the grants from the general project of medicine and health in Zhejiang Province of China (2015KYA142; 2018KY106), the Key Research and Development Program of Zhejiang Province (2017C03022) and the National Natural Science Foundation of China (81701514).The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. We have no competing interests to declare.TRIAL REGISTRATION NUMBERISRCTN26300668
      PubDate: 2017-10-13
  • Low serum progesterone on the day of embryo transfer is associated with a
           diminished ongoing pregnancy rate in oocyte donation cycles after
           artificial endometrial preparation: a prospective study
    • Authors: Labarta E; Mariani G, Holtmann N, et al.
      Abstract: STUDY QUESTIONIs there a relationship between serum progesterone (P) and endometrial volume on the day of embryo transfer (ET) with ongoing pregnancy rate (OPR) in artificial endometrium preparation cycles'SUMMARY ANSWERPatients with serum P < 9.2 ng/ml on the day of ET had a significantly lower OPR but endometrial volume was not related with OPR.WHAT IS KNOWN ALREADYA window of optimal serum P levels during the embryo implantation period has been described in artificial endometrium preparation cycles. A very low endometrial volume is related to poor reproductive outcome.STUDY DESIGN, SIZE, DURATIONProspective cohort study with 244 patients who underwent ET in an oocyte donation cycle after an artificial endometrial preparation cycle with estradiol valerate and vaginal micronized progesterone (400 mg/12 h). The study period went from 22 February 2016 to 25 October 2016 (8 months). Sample size was calculated to detect a 20% difference in OPR (35–55%) between two groups according to serum P levels in a two-sided test (80% statistical power, 95% confidence interval (CI)).PARTICIPANTS/MATERIALS, SETTING, METHODSPatients undergoing their first/second oocyte donation cycle, aged <50, BMI < 30 kg/m2, triple layer endometrium >6.5 mm and 1–2 good quality transferred blastocysts. A private infertility centre. Serum P determination and 3D ultrasound of uterine cavity were performed on the day of ET. Endometrial volume measurements were taken using a virtual organ computer-aided analysis (VOCAL™) system. The primary endpoint was OPR beyond pregnancy week 12.MAIN RESULTS AND ROLE OF CHANCEAbout 211 of the 244 recruited patients fulfilled all the inclusion/exclusion criteria. Mean serum P on the day of embryo transfer was 12.7 ± 5.4 ng/ml (Centiles 25, 9.2; 50, 11.8; 75,15.8).OPRs according to serum P quartiles were: Q1: 32.7%; Q2: 49.1%; Q3: 58.5%; Q4: 50.9%. The OPR of Q1 was significantly lower than Q2–Q4: 32.7% versus 52.8%; P = 0.016; RR (95% CI): 0.62 (0.41–0.94). The mean endometrial volume was 3.4 ± 1.9 ml. Serum P on the day of ET did not correlate with endometrial volume. A logistic regression analysis, adjusted for all the potential confounders, showed that OPR significantly lowered between women with serum P < 9.2 ng/ml versus ≥9.2 ng/ml (OR: 0.297; 95%CI: 0.113–0.779); P = 0.013. The ROC curve showed a significant predictive value of serum P levels on the day of ET for OPR, with an AUC (95%CI) = 0.59 (0.51–0.67).LIMITATIONS, REASONS FOR CAUTIONOnly the women with normal uterine cavity, appropriate endometrial thickness and good quality blastocysts transfer were included. Extrapolation to an unselected population or to other routes and/or doses of administering P needs to be validated. The role of endometrial volume could not be fully defined as very few patients presented a very low volume.WIDER IMPLICATIONS OF THE FINDINGSThe present study suggests a minimum threshold of serum P values on the day of ET that needs to be reached in artificial endometrial preparation cycles to optimize outcome. No upper threshold could be defined.STUDY FUNDING/COMPETING INTEREST(S)None.TRIAL REGISTRATION NUMBERNCT02696694
      PubDate: 2017-10-13
  • Insulin resistance in a large cohort of women with polycystic ovary
           syndrome: a comparison between euglycaemic-hyperinsulinaemic clamp and
           surrogate indexes
    • Authors: Tosi F; Bonora E, Moghetti P.
      Abstract: STUDY QUESTIONCould surrogate indexes identify insulin resistant individuals among women with polycystic ovary syndrome (PCOS)'SUMMARY ANSWERSurrogate indexes may be able to rule in, but not rule out, insulin resistance in women with PCOS.WHAT IS KNOWN ALREADYInsulin resistance is a typical finding of women with PCOS and most clinical information on this issue is based upon surrogate indexes of insulin resistance. However, data on the performance of these indexes in PCOS women are very limited.STUDY DESIGN SIZE, DURATIONA retrospective analysis of 406 women referred to our outpatient clinic for hyperandrogenism and/or menstrual dysfunction and submitted to hyperinsulinemic euglycaemic clamp between 1998 and 2015.PARTICIPANTS/MATERIALS, SETTING, METHODSIn total, 375 of these women had PCOS by the Rotterdam criteria and were included in the study. Six surrogate indexes of insulin sensitivity were calculated from glucose and insulin levels, either at fasting (homeostasis model assessment (HOMA), glucose/insulin (G/I) ratio and quantitative insulin sensitivity check index (QUICKI)) or after oral glucose load (Gutt, Stumvoll0–120 and Matsuda).MAIN RESULTS AND THE ROLE OF CHANCEOverall, insulin resistance, as identified by the M-clamp value, was found in 74.9% of these women. The percentage was 59.3% in normal-weight vs 77.5% in overweight and 93.9% in obese subjects. All surrogate indexes were highly correlated with the M-clamp values. However, their ability to identify insulin resistant individuals was limited, in terms of sensitivity and especially in normal-weight subjects. ROC analysis showed similar performances of these indexes (AUC values 0.782–0.817).LIMITATIONS REASONS FOR CAUTIONPotential referral bias of PCOS patients may have caused overestimation of the prevalence of insulin resistance in these women.WIDER IMPLICATIONS OF THE FINDINGSBy using surrogate indexes many subjects with PCOS may be erroneously diagnosed as insulin sensitive, especially among normal-weight women. These indexes can be used to rule in, but not rule out, insulin resistance in PCOS.STUDY FUNDING/COMPETING INTEREST(S)Academic grants to P. Moghetti from the University of Verona. All authors declare no conflict of interest.TRIAL REGISTRATION NUMBERN/A.
      PubDate: 2017-10-13
  • Chromosomal abnormalities in 1663 infertile men with azoospermia: the
           clinical consequences
    • Authors: Donker R; Vloeberghs V, Groen H, et al.
      Abstract: STUDY QUESTIONWhat is the prevalence of chromosomal abnormalities in azoospermic men and what are the clinical consequences in terms of increased risk for absent spermatogenesis, miscarriages and offspring with congenital malformations'SUMMARY ANSWERThe prevalence of chromosomal abnormalities in azoospermia was 14.4%, and the number of azoospermic men needed to be screened (NNS) to identify one man with a chromosomal abnormality with increased risk for absence of spermatogenesis was 72, to prevent one miscarriage 370–739 and to prevent one child with congenital malformations 4751–23 757.WHAT IS KNOWN ALREADYInfertility guidelines worldwide advise screening of non-iatrogenic azoospermic men for chromosomal abnormalities, but only few data are available on the clinical consequences of this screening strategy.STUDY DESIGN, SIZE, DURATIONThis retrospective multicentre cross-sectional study of non-iatrogenic azoospermic men was performed at the University Hospital Brussels, Belgium, and the University Medical Centre Groningen, The Netherlands, between January 2000 and July 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSAnalysis of clinical registries retrospectively identified 1663 non-iatrogenic azoospermic men with available results of karyotyping and FSH serum levels. Iatrogenic azoospermia was an exclusion criterion, defined as azoospermia after spermatotoxic medical treatment, exogenous androgen suppletion or vasectomy and/or vasovasostomy. Also, men with a clinical diagnosis of anejaculation or hypogonadotropic hypo-androgenism and/or FSH values <1.0 U/l were excluded. Chromosomal abnormalities were categorized according to their (theoretical) impact on clinical consequences for the patient (i.e. an increased risk for absence of spermatogenesis) and adverse pregnancy outcomes (i.e. miscarriage or offspring with congenital malformations), in both normogonadotropic (FSH < 10 U/l) and hypergonadotropic (FSH ≥ 10 U/l) azoospermia. We estimated the NNS for chromosomal abnormalities to identify one man with absence of spermatogenesis and to prevent one miscarriage or one child with congenital malformations, and calculated the surgical sperm retrieval rates per chromosomal abnormality.MAIN RESULTS AND THE ROLE OF CHANCEThe overall prevalence of chromosomal abnormalities in azoospermia was 14.4% (95% CI 12.7–16.1%), its prevalence being higher in hypergonadotropic azoospermia (20.2%, 95% CI 17.8–22.7%) compared to normogonadotropic azoospermia (4.9%, 95% CI 3.2–6.6%, P < 0.001). Klinefelter syndrome accounted for 83% (95% CI 77–87%) of abnormalities in hypergonadotropic azoospermia. The NNS to identify one man with increased risk for absence of spermatogenesis was 72, to prevent one miscarriage 370–739, and to prevent one child with congenital malformations 4751–23 757. There was no clinically significant difference in NNS between men with normogonadotropic and hypergonadotropic azoospermia. The surgical sperm retrieval rate was significantly higher in azoospermic men with a normal karyotype (60%, 95% CI 57.7–63.1%) compared to men with a chromosomal abnormality (32%, 95% CI 25.9–39.0%, P < 0.001). The sperm retrieval rate in Klinefelter syndrome was 28% (95% CI 20.7–35.0%).LIMITATIONS, REASONS FOR CAUTIONThe absolute number of chromosomal abnormalities associated with clinical consequences and adverse pregnancy outcomes in our study was limited, thereby increasing the role of chance. Further, as there are currently no large series on outcomes of pregnancies in men with chromosomal abnormalities, our conclusions are partly based on assumptions derived from the literature.WIDER IMPLICATIONS OF THE FINDINGSThe NNS found can be used in future cost-effectiveness studies and the evaluation of current guidelines on karyotyping in non-iatrogenic azoospermia.STUDY FUNDING/COMPETING INTEREST(S)None to declare.
      PubDate: 2017-10-13
  • New debate: is it time for infertility weight-loss programmes to be
    • Authors: Best D; Avenell A, Bhattacharya S, et al.
      Abstract: With obesity on the rise in the general population, it has also become more prevalent among people of reproductive age. Weight loss has shown benefits in overweight women and men experiencing fertility problems. However, the existing weight-loss interventions for individuals with infertility are associated with high drop-out rates and limited success. In this article, we argue for the development of weight-loss programmes targeting couples, as couples are routinely seen in fertility clinics, rather than individuals. Couples may have correlated weights, and similar eating and activity patterns. Involving both partners may facilitate mutual support, behaviour change, weight loss and programme continuation, at very little additional cost. A successful couple-based intervention could improve the chances of achieving pregnancy and delivering a healthy baby, with a reduction in pregnancy complications. In the longer run, both partners and their baby could benefit from maintained behaviour change with better health across the lifespan. We conclude that there is a need for research to systematically develop a couple-based weight-loss intervention with state-of-the-art design that is tailored to both partners’ needs.
      PubDate: 2017-10-12
  • Development of the testis in pre-pubertal boys with cancer after biopsy
           for fertility preservation
    • Authors: Uijldert M; Meißner A, de Melker A, et al.
      Abstract: STUDY QUESTIONIs testicular growth affected by a testicular biopsy intended for fertility preservation in pre-pubertal boys with cancer'SUMMARY ANSWERTesticular growth of the biopsied testis is not impeded in comparison to the non-biopsied contralateral testis up until 1 year after surgery.WHAT IS KNOWN ALREADYFertility preservation in pre-pubertal boys by means of testicular biopsy has been conducted for more than 15 years. Although immediate adverse effects of testicular biopsy are rare (1%), no data exist on the effect of biopsy on testicular growth.STUDY DESIGN, SIZE, DURATIONIn this prospective cohort study, between March 2011 and February 2017, 93 parents of pre-pubertal boys were offered cryopreservation of testicular tissue of their son, of whom 78 consented. Sixty-four boys were included in this follow-up study.PARTICIPANTS/MATERIALS, SETTING, METHODSAll boys with cancer at the paediatric oncology department of the Academic Medical Center (AMC) who needed gonadotoxic therapy and were unable to ejaculate were offered cryopreservation of testicular tissue prior to treatment. By testicular ultrasound before and after biopsy (1, 6 and 12 months after biopsy), volume and parenchymal abnormalities were assessed. Data were analysed using mixed-effects modelling.MAIN RESULTS AND THE ROLE OF CHANCEOf the 64 included boys all were followed up at 1 month, 58 at 6 months and 55 at 12 months. Mean testicular volumes after 1, 6 and 12 months after biopsy were 1.7 ± 2.1, 1.7 ± 2.2 and 1.9 ± 2.4 for the biopsied testis and 1.8 ± 2.2, 1.8 ± 2.3 and 2.0 ± 2.2 for the non-biopsied testis, respectively. Biopsy of the testis did not have a significant impact on testicular growth. Immediate adverse effects of the biopsy, i.e. wound infections, were seen in 3/78 boys (3.8%).LIMITATIONS, REASONS FOR CAUTIONAlthough it is the largest cohort available to date, the number of patients included in our follow-up is still relatively small. A larger cohort would be able to evaluate growth more precisely. Follow-up was discontinued in a significant portion of boys, 12/76 (15.8%), mainly because of death due to primary illness but also because they could not be reached or declined further follow-up.WIDER IMPLICATIONS OF THE FINDINGSThese reassuring data may be used in counselling future boys who are eligible for fertility preservation and their parents.STUDY FUNDING/COMPETING INTEREST(S)Study funded by KIKA Foundation (Kika 86), Grant from the Netherlands Organisation for Health Research and Development (ZonMW TAS-116003002). The authors declare no conflict of interest.TRIAL REGISTRATION NUMBERCCMO-register: NL27690.000.09
      PubDate: 2017-10-12
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