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Publisher: Oxford University Press   (Total: 372 journals)

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Showing 1 - 200 of 372 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 65, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 86, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 18, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 146, 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: 169, 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: 9, 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: 15, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 21)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 29, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 48, 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: 17, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 55, 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: 19)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 13)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 42, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 51, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 283, 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: 20, 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: 17, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 159, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 64, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 68, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 43, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 33, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 26, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 580, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 86, 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: 30)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 61, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 9, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 9, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal   (Followers: 2)
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: 44, 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: 5, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 4)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 8, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 25, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 62, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 3, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, 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: 27)
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: 8, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 13)
Diplomatic History     Hybrid Journal   (Followers: 19, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 5, 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: 39, 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: 14, 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: 3)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, 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: 54, 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: 9, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 171, 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: 20, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 9, 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: 40, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 10)
Family Practice     Hybrid Journal   (Followers: 14, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 10, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 22, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 27, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 23, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 14, 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: 11, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 34, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 22, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 54, 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: 24, 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: 28, 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: 8, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 72, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 16, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 60, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 51, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 12)
ILAR J.     Hybrid Journal   (Followers: 2, 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   (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: 10, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 34, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 7, 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: 6, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 56, 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: 33, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 63, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 183, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 30, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, 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: 35, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 12, 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: 35, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 22, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 42, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 20, 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: 1, 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: 45, 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: 14, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 4, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 41, SJR: 1.341, h-index: 96)
J. of Burn Care & Research     Full-text available via subscription   (Followers: 9, SJR: 0.713, h-index: 57)
J. of Chromatographic Science     Hybrid Journal   (Followers: 18, 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: 35, 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: 41, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 9, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 8, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 17, 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: 21, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 20)
J. of Experimental Botany     Hybrid Journal   (Followers: 13, 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: 5)
J. of Heredity     Hybrid Journal   (Followers: 3, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 8, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 16, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 40, SJR: 4, h-index: 209)

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Journal Cover Human Reproduction
  [SJR: 2.271]   [H-I: 179]   [72 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  [372 journals]
  • ‘Man Up’: the importance and strategy for placing male reproductive
           health centre stage in the political and research agenda
    • Authors: Barratt C; De Jonge C, Sharpe R.
      Pages: 541 - 545
      Abstract: Approximately 1 in 20 young men today have sperm counts low enough to impair fertility, whereas this may not have been the case historically. The cause(s) of such a decline in male reproductive health is unknown, despite it being a global health issue. Concomitantly, little progress has been made in answering fundamental questions in andrology or in developing new diagnostic tools or alternative management strategies to ICSI in infertile men. We advocate formulation of a detailed roadmap for male reproductive health to facilitate development of a research agenda that highlights the present unmet needs and key unanswered questions, and seeks to deliver effective funding and investment to address them. This vision we term ‘a Male Reproductive Health Ecosystem’.
      PubDate: Thu, 08 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey020
      Issue No: Vol. 33, No. 4 (2018)
  • Developmental plasticity and its relevance to assisted human reproduction
    • Authors: Roseboom T.
      Pages: 546 - 552
      Abstract: The advent of assisted reproduction has allowed the conception of millions of individuals who otherwise would not have existed. Although most ART children are born healthy, there is increasing awareness of the plasticity of the human embryo causing concerns about potential long-term consequences of ART for the growth, development and health of this growing population of individuals. Evidence from studies in animals and humans suggest that physiology and metabolism may be permanently affected by ART. It suggests that ART children may be at increased risk of later cardiometabolic diseases. Part of this increased susceptibility to cardiometabolic diseases seems to be due to parental predisposition, while part of the increased susceptibility seems to be due to the ART procedure itself. Due to the fast development of new techniques in ART, it is unclear whether newer techniques are associated with similar risks. There is evidence to suggest that the newer techniques are safer, but the rapid developments in reproductive medicine and ever increasing indications for ART make it difficult to draw conclusions. Until more is known about the effectiveness and safety of ART for the broader indications in which ART is currently used, caution in using ART is mandatory.Further progress could be made if long-term follow-up studies were included in the development of new ART techniques. Harmonization of measurements in human and animal studies of ART would allow faster scientific progress and less scientific waste. Also, including more details of the ART procedures in ART registries and allowing follow up of ART children through linking registries with already collected data from perinatal registries, child health clinics and schools would help to provide a better understanding of the growth, development and health of the growing population of ART children. Ultimately, these studies will provide the much needed information on how to provide ART children with the best possible start in life.
      PubDate: Wed, 21 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey034
      Issue No: Vol. 33, No. 4 (2018)
  • Accuracy of human sperm DNA oxidation quantification and threshold
           determination using an 8-OHdG immuno-detection assay
    • Authors: Vorilhon S; Brugnon F, Kocer A, et al.
      Pages: 553 - 562
      Abstract: STUDY QUESTIONCan a discriminant threshold be determined for human sperm DNA oxidation'SUMMARY ANSWERA discriminant threshold was found with 65.8% of 8-hydroxy-2’-deoxyguanosine (8-OHdG)-positive sperm cells and a mean intensity of fluorescence (MIF) of 552 arbitrary units.WHAT IS KNOWN ALREADYOxidative stress is known to interfere with sperm quality and fertilizing capacity. However, current practice does not include the routine determination of oxidative DNA damage in spermatozoa; optimized consensus protocols are lacking and no thresholds of normality have been established.STUDY DESIGN, SIZE, DURATIONIntra- and inter-method comparisons between four protocols (I–IV) were conducted to determine the most relevant and efficient means of assessing human sperm 8-OHdG content. Tests of assay repeatability, specificity, sensitivity and stability were performed to validate an optimized methodology for routine diagnostic use.PARTICIPANTS/MATERIALS, SETTING, METHODSThis prospective study compared three immuno-detection methods including immunocytochemistry, fluorescence microscopy and flow cytometry. Sperm DNA oxidation for 80 patients was determined relative to semen parameters and clinical conditions, using the selected immuno-detection protocol in comparison with a commercial kit. These patients (age 35 ± 1 years: mean ± SEM) presented with normozoospermic (n = 40) or altered parameters (necro- or/and astheno- or/and teratozoospermia or/and leukocytospermia).MAIN RESULTS AND THE ROLE OF CHANCESignificant positive Pearson and Spearman correlations were determined for 8-OHdG values and sperm parameters using protocol III. A notable high and positive correlation was revealed for MIF with BMI and leukocyte concentration. Protocol III was the most discriminating method regarding assay repeatability, specificity, sensitivity, stability and reliability for sperm parameter alterations, in particular leukocytospermia according to parametric or non-parametric tests, effect-size determinations and factorial analysis such as principal component analysis and factor discriminant analysis. Of interest is that 39% of the subjects with ‘pathological’ sperm DNA oxidation values were normozoospermic.LIMITATIONS, REASONS FOR CAUTIONThe oligozoospermic population was not evaluated in this study because insufficient material was available to carry out the comparisons. However, spermatozoa concentration was taken into account in the statistical analysis.WIDER IMPLICATIONS OF THE FINDINGSOur study is the first validation of a protocol to determine a discriminant threshold for human sperm DNA oxidation. The protocol’s detection accuracy for 8-OHdG human sperm DNA residues, stability over time, and relationship to human sperm quality were demonstrated. The assay should find application in the diagnosis of male factor infertility associated with oxidative stress.STUDY FUNDING/COMPETING INTEREST(S)This work was funded by institutional grants from the CNRS, INSERM and Université Clermont Auvergne (to J.R.D.) and by Clermont-Ferrand Hospital-CECOS research funds (to L.J. and F.B.). P.G., A.M., R.J.A. and J.D. are, respectively, CEO, scientific director and scientific advisors of a US-based biotech company (Celloxess, Princeton, NJ, USA) involved in preventative medicine with a focus on the generation of antioxidant oral supplements.
      PubDate: Fri, 23 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey038
      Issue No: Vol. 33, No. 4 (2018)
  • The significance of human spermatozoa vacuoles can be elucidated by a
           novel procedure of array comparative genomic hybridization
    • Authors: Berkovitz A; Dekel Y, Goldstein R, et al.
      Pages: 563 - 571
      Abstract: STUDY QUESTIONIs there an association between spermatozoon genomic stability and vacuolar morphology and location'SUMMARY ANSWERThe genomic stability of spermatozoa is associated with specific characteristics of vacuolar morphology (depth) and location (cellular compartment, i.e. nucleus and equatorial region).WHAT IS KNOWN ALREADYGenetic anomalies in sperm are correlated with semen abnormalities, yet the advantage of morphologically based selection of spermatozoa for IVF according to current criteria is controversial. Selection criteria based on the number of vacuoles and their size have been proposed and are widely applied. Nevertheless, it has not improved the ICSI success rates, suggesting the currently used vacuole criteria are incomplete.STUDY DESIGN, SIZE, DURATIONNormal sperm according to Motile Sperm Organelle Morphology Examination criteria (MSOME) and common vacuole grading were evaluated. An additional evaluation of sperm vacuole morphology according to novel vacuole criteria (i.e. location and depth) was conducted. An assessment to align these specific vacuolar morphology features with genomic stability was conducted among spermatozoa from infertile patients and healthy fertile donors aged 24–38 between June 2015 and July 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSSingle spermatozoa (n = 53) from 16 infertile patients and 14 fertile donors were morphologically and genetically evaluated. Each spermatozoon was examined morphologically, by ultra-magnification ×6300, and genetically by a novel comparative genomic hybridization protocol, without the use of reference DNA, to assess chromosomal instability as evident by copy number variations (CNV).MAIN RESULTS AND THE ROLE OF CHANCEWe established an association between genomic stability and vacuolar morphology as a base for a new classification according to novel vacuolar criteria, specifically depth and location. Genomic instability was found to be related to these two main features of vacuoles and, surprisingly not to the number and size of vacuoles as in the previously proposed classifications. High CNV spermatozoa were characterized by vacuoles located in the nucleus and/or equatorial segment or by deep vacuoles, while, low CNV spermatozoa were characterized by a complete lack of vacuoles or non-deep vacuoles not located in the nucleus/equatorial segment. A putative threshold of ~265 CNV was deduced to distinguish between genetically stable and unstable spermatozoa, and 94% of the tested spermatozoa segregated accordingly.LIMITATIONS REASONS FOR CAUTIONA relatively small sample of spermatozoa were examined—53 in total. However, the association between vacuoles location and morphology and genomic stability was significant. This is the first study evaluating spermatozoon genomic stability with respect to vacuole morphology according to novel vacuole criteria (i.e. location and depth) and further investigation is warranted to verify the value of these criteria in larger sample size clinical studies.WIDER IMPLICATIONS OF THE FINDINGSOur results, which are based on spermatozoon vacuoles morphological classification and genomic parameters, indicate an association between vacuoles morphology and location and genomic stability. The data presented herein suggest the existence of subpopulations of spermatozoa potentially appropriate for IVF–ICSI, as they appear normal according to the current MSOME and vacuoles classification, however they are almost certainly genetically damaged. As current criteria have yet to achieve an unequivocal evaluation of the implantation potential of a given spermatozoon, we propose novel criteria, based on specific vacuolar morphological traits; depth and location, as these were found aligned with genomic findings.STUDY FUNDING/COMPETING INTEREST(S)No funding was received for this study. The authors have no conflict of interest to declare.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Tue, 06 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey019
      Issue No: Vol. 33, No. 4 (2018)
  • Cell-free fetal DNA testing in singleton IVF conceptions
    • Authors: Lee T; Rolnik D, Menezes M, et al.
      Pages: 572 - 578
      Abstract: STUDY QUESTIONAre fetal fraction, test failure rate and positive predictive value (PPV) of cell-free fetal DNA (cffDNA) testing different in singleton IVF conceptions compared to spontaneous conceptions'SUMMARY ANSWERFetal fraction is significantly lower; test failure rate is higher and PPV of cffDNA testing is lower in singleton pregnancies conceived by IVF than those conceived spontaneously.WHAT IS ALREADY KNOWNcffDNA testing, which analyses circulating cffDNA in maternal blood, has very high accuracy for detection of trisomy 21 in the general obstetric population. Focused and conclusive evidence regarding the test characteristics of cffDNA testing in IVF conceived pregnancies is lacking.STUDY DESIGN, SIZE, DURATIONThis was a retrospective cohort study including spontaneously and IVF conceived singleton pregnancies collected consecutively between April 2013 and November 2016. A total of 4633 spontaneously conceived and 992 IVF pregnancies were included.PARTICIPANTS/MATERIALS, SETTING, METHODSThe study was performed at an obstetric and gynecological ultrasound clinic in Melbourne, Australia. Participants had screening for trisomies 21, 18 and 13, as well as sex chromosome aneuploidies (SCA) performed with cffDNA testing after 10 weeks’ gestation. Multivariate regression analysis was used to determine significant predictors of logarithmically transformed fetal fraction and test failure. Comparison of test characteristics between study groups was performed adopting a significance level of 5%.MAIN RESULTS AND THE ROLE OF CHANCEMedian fetal fraction was lower (10.3% [interquartile range (IQR), 7.7–13.5] versus 11.9% [IQR, 9.1–15.0]; P = 0.005), test failure rate was higher (5.2 versus 2.2%; P < 0.001) and positive predictive value (PPV) for trisomies 18, 13 and SCA was poorer in IVF pregnancies compared to those spontaneously conceived. Multivariate linear regression analysis demonstrated that IVF conception, increased BMI, earlier gestational age and South and East Asian ethnicities were independent predictors of lower fetal fraction. Multiple logistic regression analysis found IVF conception and increased BMI to be independently associated with test failure. PPV was high for trisomy 21 in IVF conception (100.0%), but was lower for other trisomies when compared with the non-IVF population.LIMITATIONS REASONS FOR CAUTIONIVF details were unascertainable for 210 cases, as the information was not available through our data collection points. Inability to karyotype some cases at high-risk for SCA, due to patients’ choice, and the occurrence of miscarriages and terminations, resulted in the exclusion of high-risk cases when calculating PPV. Pregnancy outcomes were not available in low-risk pregnancies and negative predictive values could not be calculated.WIDER IMPLICATIONS OF THE FINDINGSThe limitations revealed by this work should be taken into account during pre-test counseling in pregnant women who conceive by IVF.STUDY FUNDING/COMPETING INTEREST(S)No external source of financial support was provided for this research. The authors report no conflicts of interest.
      PubDate: Thu, 15 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey033
      Issue No: Vol. 33, No. 4 (2018)
  • Recurrent pregnancy loss evaluation combined with 24-chromosome microarray
           of miscarriage tissue provides a probable or definite cause of pregnancy
           loss in over 90% of patients
    • Authors: Popescu F; Jaslow C, Kutteh W.
      Pages: 579 - 587
      Abstract: STUDY QUESTIONWill the addition of 24-chromosome microarray analysis on miscarriage tissue combined with the standard American Society for Reproductive Medicine (ASRM) evaluation for recurrent miscarriage explain most losses'SUMMARY ANSWEROver 90% of patients with recurrent pregnancy loss (RPL) will have a probable or definitive cause identified when combining genetic testing on miscarriage tissue with the standard ASRM evaluation for recurrent miscarriage.WHAT IS KNOWN ALREADYRPL is estimated to occur in 2–4% of reproductive age couples. A probable cause can be identified in approximately 50% of patients after an ASRM recommended workup including an evaluation for parental chromosomal abnormalities, congenital and acquired uterine anomalies, endocrine imbalances and autoimmune factors including antiphospholipid syndrome.STUDY DESIGN, SIZE, DURATIONSingle-center, prospective cohort study that included 100 patients seen in a private RPL clinic from 2014 to 2017. All 100 women had two or more pregnancy losses, a complete evaluation for RPL as defined by the ASRM, and miscarriage tissue evaluated by 24-chromosome microarray analysis after their second or subsequent miscarriage.PARTICIPANTS/MATERIALS, SETTING, METHODSFrequencies of abnormal results for evidence-based diagnostic tests considered definite or probable causes of RPL (karyotyping for parental chromosomal abnormalities, and 24-chromosome microarray evaluation for products of conception (POC); pelvic sonohysterography, hysterosalpingogram, or hysteroscopy for uterine anomalies; immunological tests for lupus anticoagulant and anticardiolipin antibodies; and blood tests for thyroid stimulating hormone (TSH), prolactin and hemoglobin A1c) were evaluated. We excluded cases where there was maternal cell contamination of the miscarriage tissue or if the ASRM evaluation was incomplete. A cost analysis for the evaluation of RPL was conducted to determine whether a proposed procedure of 24-chromome microarray evaluation followed by an ASRM RPL workup (for those RPL patients who had a normal 24-chromosome microarray evaluation) was more cost-efficient than conducting ASRM RPL workups on RPL patients followed by 24-chromosome microarray analysis (for those RPL patients who had a normal RPL workup).MAIN RESULTS AND THE ROLE OF CHANCEA definite or probable cause of pregnancy loss was identified in the vast majority (95/100; 95%) of RPL patients when a 24-chromosome pair microarray evaluation of POC testing is combined with the standard ASRM RPL workup evaluation at the time of the second or subsequent loss. The ASRM RPL workup identified an abnormality and a probable explanation for pregnancy loss in only 45/100 or 45% of all patients. A definite abnormality was identified in 67/100 patients or 67% when initial testing was performed using 24-chromosome microarray analyses on the miscarriage tissue. Only 5/100 (5%) patients, who had a euploid loss and a normal ASRM RPL workup, had a pregnancy loss without a probable or definitive cause identified. All other losses were explained by an abnormal 24-chromosome microarray analysis of the miscarriage tissue, an abnormal finding of the RPL workup, or a combination of both. Results from the cost analysis indicated that an initial approach of using a 24-chromosome microarray analysis on miscarriage tissue resulted in a 50% savings in cost to the health care system and to the patient.LIMITATIONS, REASONS FOR CAUTIONThis is a single-center study on a small group of well-characterized women with RPL. There was an incomplete follow-up on subsequent pregnancy outcomes after evaluation, however this should not affect our principal results. The maternal age of patients varied from 26 to 45 years old. More aneuploid pregnancy losses would be expected in older women, particularly over the age of 35 years old.WIDER IMPLICATIONS OF THE FINDINGSEvaluation of POC using 24-chromosome microarray analysis adds significantly to the ASRM recommended evaluation of RPL. Genetic evaluation on miscarriage tissue obtained at the time of the second and subsequent pregnancy losses should be offered to all couples with two or more consecutive pregnancy losses. The combination of a genetic evaluation on miscarriage tissue with an evidence-based evaluation for RPL will identify a probable or definitive cause in over 90% of miscarriages.STUDY FUNDING/COMPETING INTEREST(S)No funding was received for this study and there are no conflicts of interest to declare.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Mon, 12 Mar 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey021
      Issue No: Vol. 33, No. 4 (2018)
  • Interleukin-34 is present at the fetal–maternal interface and induces
           immunoregulatory macrophages of a decidual phenotype in vitro
    • Authors: Lindau R; Mehta R, Lash G, et al.
      Pages: 588 - 599
      Abstract: STUDY QUESTIONIs the newly discovered cytokine interleukin (IL)-34 expressed at the human fetal–maternal interface in order to influence polarization of monocytes into macrophages of a decidual immunoregulatory phenotype'SUMMARY ANSWERIL-34 was found to be present at the fetal–maternal interface, in both fetal placenta and maternal decidua, and it was able to polarize monocytes into macrophages of a decidual phenotype.WHAT IS KNOWN ALREADYIL-34 was shown to bind to the same receptor as macrophage-colony stimulating factor (M-CSF), which has an important immunomodulatory role at the fetal–maternal interface, for example by polarizing decidual macrophages to an M2-like regulatory phenotype. IL-34 is known to regulate macrophage subsets, such as microglia and Langerhans cells, but its presence at the fetal–maternal interface is unknown.STUDY DESIGN, SIZE, DURATIONThe presence of IL-34 at the fetal–maternal interface was evaluated by immunohistochemistry (IHC) and ELISA in placental and decidual tissues as well as in isolated trophoblast cells and decidual stromal cells obtained from first trimester elective surgical terminations of pregnancy (n = 49). IL-34 expression was also assessed in third trimester placental biopsies from women with (n = 21) or without (n = 15) pre-eclampsia. The effect of IL-34 on macrophage polarization was evaluated in an in vitro model of blood monocytes obtained from healthy volunteers (n = 14). In this model, granulocyte macrophage-colony stimulating factor (GM-CSF) serves as a growth factor for M1-like polarization, and M-CSF as a growth factor for M2-like polarization.PARTICIPANTS/MATERIALS, SETTING, METHODSFirst trimester placental and decidual tissues were obtained from elective pregnancy terminations. Placental biopsies were obtained from women with pre-eclampsia and matched controls in the delivery ward. Polarization of macrophages in vitro was determined by flow-cytometric phenotyping and secretion of cytokines and chemokines in cell-free supernatants by multiplex bead assay.MAIN RESULTS AND THE ROLE OF CHANCEOur study shows that IL-34 is produced at the fetal–maternal interface by both placental cyto- and syncytiotrophoblasts and decidual stromal cells. We also show that IL-34, in vitro, is able to polarize blood monocytes into macrophages with a phenotype (CD14highCD163+CD209+) and cytokine secretion pattern similar to that of decidual macrophages. The IL-34-induced phenotype was similar, but not identical to the phenotype induced by M-CSF, and both IL-34- and M-CSF-induced macrophages were significantly different (P < 0.05–0.0001 depending on marker) from GM-CSF-polarized M1-like macrophages. Our findings suggest that IL-34 is involved in the establishment of the tolerant milieu found at the fetal–maternal interface by skewing polarization of macrophages into a regulatory phenotype.LIMITATIONS, REASONS FOR CAUTIONAlthough it is clear that IL-34 is present at the fetal–maternal interface and polarizes macrophages in vitro, its precise role in vivo remains to be established.WIDER IMPLICATIONS OF THE FINDINGSThe recently discovered cytokine IL-34 is present at the fetal–maternal interface and has immunomodulatory properties with regard to induction of decidual macrophages, which are important for a healthy pregnancy. Knowledge of growth factors related to macrophage polarization can potentially be translated to treatment of pregnancy complications involving dysregulation of this process.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by grants from the Medical Research Council (Grant K2013-61X-22310-01-04), the Research Council of South-East Sweden (FORSS), and the County Council of Östergötland, Sweden. No author has any conflicts of interest to declare.
      PubDate: Fri, 23 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey037
      Issue No: Vol. 33, No. 4 (2018)
  • ESHRE/ESGE female genital tract anomalies classification system—the
           potential impact of discarding arcuate uterus on clinical practice
    • Authors: Knez J; Saridogan E, Van Den Bosch T, et al.
      Pages: 600 - 606
      Abstract: STUDY QUESTIONWhat would be a potential impact of implementing the new ESHRE/European Society of Gynaecological Endoscopy (ESGE) female genital anomalies classification system on the management of women with previous diagnosis of arcuate uteri based on the modified American Society for Reproductive Medicine (ASRM) criteria'SUMMARY ANSWERA significant number of women with previous diagnosis of arcuate uteri are reclassified as having partial septate uteri according to the new ESHRE/ESGE classification system which may increase the number of remedial surgical procedures.WHAT IS KNOWN ALREADYThe ESHRE/ESGE classification system has defined measurement techniques, reference points and specific cut-offs to facilitate the differentiation between normal and septate uteri. These criteria have been arbitrarily defined and they rely on the measurement of uterine wall thickness and depth of distortion of uterine fundus.STUDY DESIGN, SIZE, DURATIONThis was a retrospective cohort study. We searched our ultrasound clinic database from January 2011 to December 2014 to identify all women diagnosed with arcuate uterus on three-dimensional ultrasound according to the modified ASRM criteria.PARTICIPANTS/MATERIALS, SETTING, METHODSFor each woman, the ultrasound images were stored in our clinical database and they were re-examined according to ESHRE/ESGE specifications. The presence and location of all acquired uterine anomalies, such as fibroids or adenomyosis was noted. We applied the two diagnostic approaches as specified by the ESHRE/ESGE classification: the main option (MO) and the alternative option (AO). We used the Kappa statistic to quantify the agreement between the two approaches. We also compared the number of previous miscarriages in women with normal and partial septate uteri according to the ESHRE/ESGE classification. Non-parametric Mann–Whitney and Kruskal–Wallis tests were used for the analyses and receiver-operating characteristic curves were constructed to assess the predictive values of the calculated uterine distortion indices for the detection of women at risk of suffering multiple pregnancy losses.MAIN RESULTS AND THE ROLE OF CHANCEWe included 270 women diagnosed with arcuate uterus in the study. In all, 77 women (28.5%, 95% confidence interval (CI) 23.1–33.9) had evidence of fibroids or adenomyosis. These abnormalities precluded the application of either proposed ESHRE/ESGE techniques to assess uterine morphology in 25 women (9.3%, 95% CI 5.8–12.7). When using the MO, 138/237 (58.2%, 95% CI 51.9–64.3) women were diagnosed with partial septate uterus compared to 61/230 (26.5%, 95% CI 21.2–32.6) women when using the AO. In 222 women in whom we were able to apply both MO and AO, there was agreement in the diagnosis of septate uterus between the two techniques in 146/222 cases (65.8%, 95% CI 59.3–71.7; Kappa 0.42, 95%CI 0.35–0.5). There was no statistical difference in the proportion of women with history of previous multiple miscarriages between those diagnosed with normal or partial septate uteri using either MO (6.2%, 95% CI 2.9–12.9 vs. 9.5%, 95% CI 5.6–15.6; P = 0.47) or AO (7.2%, 95% CI 4.2–12.1 vs. 11.7%, 95% CI 5.8–22.2; P = 0.29).LIMITATIONS, REASONS FOR CAUTIONThis study was retrospective in nature and the definition of arcuate uterus used in the study is not universally accepted. The reproductive history data were collected retrospectively and therefore may be prone to bias.WIDER IMPLICATIONS OF THE FINDINGSThere are methodological weaknesses in the new ESHRE/ESGE classification system which would need to be addressed in future revisions. There was no significant difference in the past reproductive outcomes between women diagnosed with normal and anomalous uteri and the clinicians should exercise caution when offering surgical correction to women diagnosed with partial septate uteri using the new ESHRE/ESGE classification.STUDY FUNDING/COMPETING INTEREST(S)No study funding was received and no competing interests are present.TRIAL REGISTRATION NUMBERN/A
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey043
      Issue No: Vol. 33, No. 4 (2018)
  • Endometriosis induces gut microbiota alterations in mice
    • Authors: Yuan M; Li D, Zhang Z, et al.
      Pages: 607 - 616
      Abstract: STUDY QUESTIONWhat happens to the gut microbiota during development of murine endometriosis'SUMMARY ANSWERMice with the persistence of endometrial lesions for 42 days develop a distinct composition of gut microbiota.WHAT IS KNOWN ALREADYDisorders in the immune system play fundamental roles in changing the intestinal microbiota. No study has used high-throughput DNA sequencing to show how endometriosis changes the gut microbiota, although endometriosis is accompanied by abnormal cytokine expression and immune cell dysfunction.STUDY DESIGN, SIZE, DURATIONThis study includes a prospective and randomized experiment on an animal endometriosis model induced via the intraperitoneal injection of endometrial tissues.PARTICIPANTS/MATERIALS, SETTING, METHODSThe mice were divided into endometriosis and mock groups and were sacrificed at four different time points for model confirmation and fecal sample collection. To detect gut microbiota, 16S ribosomal-RNA gene sequencing was performed. Alpha diversity was used to analyze the complexity and species diversity of the samples through six indices. Beta diversity analysis was utilized to evaluate the differences in species complexity. Principal coordinate analysis and unweighted pair-group method with arithmetic means clustering were performed to determine the clustering features. The microbial features differentiating the fecal microbiota were characterized by linear discriminant analysis effect size method.MAIN RESULTS AND THE ROLE OF CHANCEThe endometriosis and mock mice shared similar diversity and richness of gut microbiota. However, different compositions of gut microbiota were detected 42 days after the modeling. Among the discriminative concrete features, the Firmicutes/Bacteroidetes ratio was elevated in mice with endometriosis, indicating that endometriosis may induce dysbiosis. Bifidobacterium, which is known as a commonly used probiotic, was also increased in mice with endometriosis.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONMore control groups should be further studied to clarify the specificity of the dysbiosis induced by endometriosis. This study was performed only on mice. Thus, additional data acquired from patients with endometriosis are needed in future research. We only detected the changes of gut microbiota at 42 days after the modeling, while the long-term effect of endometriosis on gut microbiota remains poorly understood. Moreover, we only revealed a single effect of endometriosis on gut microbiota.WIDER IMPLICATIONS OF THE FINDINGSThis study provided the first comprehensive data on the association of endometriosis and gut microbiota from high-throughput sequencing technology. The gut microbiota changed with the development of endometriosis in a murine model. The communication between the host and the gut microbiota is bidirectional, and further studies should be performed to clarify their relationship.STUDY FUNDING/COMPETING INTEREST(S)This research was supported by Grant (81571417) from the National Science Foundation of China and Grant (2015GSF118092) from the Technology Development Plan of Shandong Province. The authors report no conflict of interest.
      PubDate: Tue, 23 Jan 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dex372
      Issue No: Vol. 33, No. 4 (2018)
  • Effect of exposure to second-hand smoke from husbands on biochemical
           hyperandrogenism, metabolic syndrome and conception rates in women with
           polycystic ovary syndrome undergoing ovulation induction
    • Authors: Li J; Wu Q, Wu X, et al.
      Pages: 617 - 625
      Abstract: STUDY QUESTIONDoes second-hand smoke (SHS) exposure from husbands have adverse effects on sex hormones, metabolic profiles, clinical phenotypes and fertility outcomes in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction'SUMMARY ANSWERSHS exposure is associated with worsened biochemical hyperandrogenism, higher incidence of metabolic syndrome and reduced conception rates in women with PCOS.WHAT IS KNOWN ALREADYSmoking in women impairs fecundity at some stages of the reproductive process including folliculogenesis, embryo transport, endometrial angiogenesis and uterine blood flow. Yet little is known about the hazard of SHS exposure in women with PCOS.STUDY DESIGN, SIZE, DURATIONThis study was a secondary analysis of the Polycystic Ovary Syndrome Acupuncture and Clomiphene Trial (PCOSAct), a large randomized controlled trial conducted at 27 hospitals from 2012 to 2015 in mainland China.PARTICIPANTS/MATERIALS, SETTING, METHODSOut of 1000 women with PCOS, SHS exposure status were available in 500 women, of whom 271 women were non-exposed and 229 exposed to cigarette smoke (170 women ≤10 cigarettes per day as low-SHS exposed and 59 women >10 cigarettes per day as high-SHS exposed). We compared circulating sex steroids, glucose and lipid metabolism, metabolic syndrome and phenotypes, fertility and obstetric outcomes between non-exposed and exposed women.MAIN RESULTS AND THE ROLE OF CHANCEWomen exposed to SHS, compared to non-exposed women, had a higher serum total testosterone (1.7 vs 1.5 nmol/L, P = 0.01), free androgen index (5.7 vs 4.0, P = 0.001) and lower sex hormone binding globulin (30.1 vs 35.6 nmol/L, P = 0.03). Metabolic syndrome, but not other phenotypes, was more frequent in exposed women as compared to non-exposed women (21.8 vs 13.3%, adjusted odds ratio (OR)=1.66; 95% CI, 1.02–2.71, P = 0.04). Ovulation rates between exposed and non-exposed groups were not significantly different (76.9 vs 82.9%, adjusted OR=0.72; 95% CI, 0.45–1.15, P = 0.17). Conception rates were significant lower in the exposed group (26.6 vs 36.9%; adjusted OR=0.61; 95% CI, 0.41–0.91; P = 0.01), while clinical pregnancy and live birth rates showed a similar trend that was not statistically significant. Gestational age, birth weight and other obstetric outcomes were not affected by SHS exposure.LIMITATIONS, REASONS FOR CAUTIONData on SHS exposure were missing in 50% of the women. We did not assay serum nicotine or cotinine levels to quantify the SHS exposure status.WIDER IMPLICATIONS OF THE FINDINGSThese data suggest that smoking partners of infertile women with PCOS who seek treatment should be advised to quit smoking.STUDY FUNDING/COMPETING INTEREST(S)Funding was provided by the National Public Welfare Projects for Chinese Medicine (201107005 and 200807002) and the National Clinical Trial Base in Chinese Medicine Special Projects (JDZX2012036 and 2015B009). There are no conflicts of interest.TRIAL REGISTRATION number: NCT01573858 and number: ChiCTR-TRC-12002081.
      PubDate: Tue, 20 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey027
      Issue No: Vol. 33, No. 4 (2018)
  • Asynchronous and pathological windows of implantation: two causes of
           recurrent implantation failure†
    • Authors: Sebastian-Leon P; Garrido N, Remohí J, et al.
      Pages: 626 - 635
      Abstract: STUDY QUESTIONIs endometrial recurrent implantation failure (RIF) only a matter of an asynchronous (displaced) window of implantation (WOI), or could it also be a pathological (disrupted) WOI'SUMMARY ANSWEROur predictive results demonstrate that both displaced and disrupted WOIs exist and can present independently or together in the same RIF patient.WHAT IS KNOWN ALREADYSince 2002, many gene expression signatures associated with endometrial receptivity and RIF have been described. Endometrial transcriptomics prediction has been applied to the human WOI in two previous studies. One study describes endometrial RIF to be the result of a temporal displacement of the WOI. The other indicates that endometrial RIF can also result from a molecularly disrupted WOI without temporal displacement.STUDY DESIGN, SIZE, DURATIONRetrospective analysis was undertaken to compare WOI endometrial transcriptomics predictions in controls (n = 72) and RIF patients (n = 43). RIF was clinically designated by the absence of implantation after four or more transfers of high quality embryos or after the placement of 10 or more embryos in multiple transfers. Endometrial tissue samples were collected from LH + 5 to LH + 8. We compared the two molecular causes of RIF to signatures currently described in the literature. We propose a new transcriptomic RIF taxonomy to fill the gap between the two hypotheses and to guide the development of clinical detection and determination of both types of RIF.PARTICIPANTS/MATERIALS, SETTING, METHODSUtilizing 115 gene expression profiles, two different predictive designs were developed: one considering RIF versus controls removing menstrual cycle timing, called the disrupted or pathological model, and another stratifying the WOI in transcriptomic profiles related to timing for predicting displacements. The predictive value of each model was compared between all signatures selected. We propose a new genomic approach that distinguishes between both types of RIF in the same sample cohort.MAIN RESULTS AND THE ROLE OF CHANCEFrom the 16 signatures analysed, we clearly predicted two causes of RIF—both a displaced WOI and an on-time but pathologically disrupted WOI. A high predictive value related to WOI profiles associated with menstrual cycle timing was found in most of the signatures. Specifically, 69% of the signatures analysed presented an accuracy higher than expected by chance in a range from 0.87 to 0.97. Displacements and disruptions were not molecularly independent, as some signatures were moderately associated with both causes. The gene and functional comparison between signatures revealed that they were not similar, although we did find functions in common and a cluster of moderate functional concordance between some of the signatures that predicted displacements (the highest Cohen's Kappa index were between 0.55 and 0.62 depending on the functional database). We propose a new transcriptomic RIF taxonomy to fill the gap between these prior studies and to establish methodology for detecting and distinguishing both types of RIF in clinical practice. Our findings indicate these two phenotypes could present independently or together in the same RIF patient. RIF patients designated by clinical criteria have been stratified transcriptomically as 18.6% with only a displaced WOI, 53.5% with a displaced and pathological WOI, 23.3% with only a disrupted WOI, and 4.7% could be a clinical RIF with non-endometrial origin. The new RIF transcriptomic taxonomy avoids menstrual cycle timing as a confounding variable that should be controlled for, distinguishing clearly between a disrupted and a displaced WOI for precision medicine in RIF.LIMITATIONS REASONS FOR CAUTIONThe main objective of this study was to use transcriptomics to detect both RIF causes and to understand the role of transcriptomic signatures in these phenotypes. The predictive value in absolute terms for each signature was not indicative in these prediction designs; instead, the comparison between signatures was most important for prediction capability in the same sample cohort for both RIF causes. Clinical follow up of the RIF taxonomies proposed has not been analysed in this study, so further prospective clinical studies are necessary to determine the prevalence and penetrance of these phenotypes.WIDER IMPLICATIONS OF THE FINDINGSThe main insight from this study is a new understanding of RIF taxonomy. Understanding how to classify RIF patients to distinguish clinically between a patient who could benefit from a personalized embryo transfer day and a patient with a disrupted WOI will enable identification and stratification for the research and development of new treatments. In addition, we demonstrate that basic research designs in endometrial transcriptomics cause masking of the study variable by the menstrual cycle timing.STUDY FUNDING/COMPETING INTEREST(S)This research has been funded by IVI-RMA; the authors do not have any competing interests.
      PubDate: Wed, 14 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey023
      Issue No: Vol. 33, No. 4 (2018)
  • A diagnostic germ cell score for immature testicular tissue at risk of
           germ cell loss
    • Authors: Heckmann L; Langenstroth-Röwer D, Pock T, et al.
      Pages: 636 - 645
      Abstract: STUDY QUESTIONCan a systematic scoring procedure provide crucial information on the status of highly heterogeneous immature human testicular tissues in the context of cryopreservation for fertility preservation'SUMMARY ANSWERWe developed a systematic histological score as a novel diagnostic tool which differentiates the patient cohort according to the status of germ cell differentiation and number of spermatogonia (normal, diminished and absent), and which could be relevant in the fertility clinic.WHAT IS KNOWN ALREADYCryopreservation of testicular tissue of immature boys is currently considered the option for future fertility restoration. However, experimental techniques for the derivation of sperm as well as valid diagnostic scoring of these immature testis tissues are not yet reported.STUDY DESIGN, SIZE, DURATIONTesticular tissues of 39 patients (aged 2–20 years) who attended our clinic for cryopreservation between 2010 and 2015 were analyzed to determine the variability of testicular tissue composition, germ cell numbers and differentiation status.PARTICIPANTS/MATERIALS, SETTING, METHODSHuman testicular tissue samples were divided into three groups. Group NT included patients suffering from diseases which do not directly affect the testes (n = 6; aged 6–14 years), group AT included patients suffering from diseases that directly affect the testes (n = 14; 2–17 years), and group KS (Klinefelter patients, n = 19; 12–20 years). Based on immunohistochemical stainings for MAGEA4, the differentiation status as well as the numbers of gonocytes, spermatogonia and spermatocytes were determined.MAIN RESULTS AND THE ROLE OF CHANCETesticular tissue samples from the NT group contained a mean of 100.3 spermatogonia/mm3 (×103). Highly heterogeneous and significantly lower mean numbers of spermatogonia were scored in testes from boys after cytotoxic exposures or with pre-existing disease (AT group: 35.7 spermatogonia/mm3 (×103); KS group: 1.8 spermatogonia/mm3 (×103)). In addition, the germ cell differentiation status was determined and revealed tissues with either spermatogonia and gonocytes, only spermatogonia, spermatogonia and spermatocytes, or all three germ cell types were present. Based on spermatogonial numbers and differentiation status, we developed a germ cell score which we applied to each individual patient sample.LIMITATIONS REASONS FOR CAUTIONNormal human testicular tissue samples are difficult to obtain for ethical reasons and the sample numbers were small. However, six such samples provide a valid baseline for the normal situation.WIDER IMPLICATIONS OF THE FINDINGSFertility preservation of immature male tissues is an emerging field and is currently offered in many specialized centers worldwide. Our diagnostic germ cell score delivers an easily applicable tool, facilitating patient counseling and thus ensuring comparability between the centers with regard to future studies.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the Funding Initiative: Translational Research, Ministry of Innovation, Science and Research, Federal State of North Rhine Westphalia (z1403ts006). The authors declare that they do not have competing financial interests.
      PubDate: Wed, 14 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey025
      Issue No: Vol. 33, No. 4 (2018)
  • The psychological well-being and prenatal bonding of gestational
    • Authors: Lamba N; Jadva V, Kadam K, et al.
      Pages: 646 - 653
      Abstract: STUDY QUESTIONHow does the psychological well-being and prenatal bonding of Indian surrogates differ from a comparison group of mothers'SUMMARY ANSWERSurrogates had higher levels of depression during pregnancy and post-birth, displayed lower emotional connection with the unborn baby, and greater care towards the healthy growth of the foetus, than the comparison group of mothers.WHAT IS ALREADY KNOWNStudies in the West have found that surrogates do not suffer long-term psychological harm. One study has shown that surrogates bond less with the foetus than expectant mothers.STUDY, DESIGN, SIZE, DURATIONThis study uses a prospective, longitudinal and cross-sectional design. Surrogates and a matched group of expectant mothers were seen twice, during 4–9 months of pregnancy and 4–6 months after the birth.PARTICIPANTS/MATERIALS, SETTING, METHODSSemi-structured interviews and standardized questionnaires were administered to 50 surrogates and 69 expectant mothers during pregnancy and 45 surrogates and 49 expectant mothers post-birth. All gestational surrogates were hosting pregnancies for international intended parents.MAIN RESULTS AND THE ROLE OF CHANCESurrogates had higher levels of depression compared to the comparison group of mothers, during pregnancy and post-birth (P < 0.02). Low social support during pregnancy, hiding surrogacy and criticism from others were found to be predictive of higher depression in surrogates post-birth (P < 0.05). Regarding prenatal bonding, surrogates interacted less with and thought less about the foetus but adopted better eating habits and were more likely to avoid unhealthy practices during pregnancy, than expectant mothers (P < 0.05). No associations were found between greater prenatal bonding and greater psychological distress during pregnancy or after relinquishment.LIMITATIONS, REASONS FOR CAUTIONAll surrogates were recruited from one clinic in Mumbai, and thus the representativeness of this sample is not known. Also, the possibility of socially desirable responding from surrogates cannot be ruled out.WIDER IMPLICATIONS OF THE FINDINGSAs this is the first study of the psychological well-being of surrogates in low-income countries, the findings have important policy implications. Providing support and counselling to surrogates, especially during pregnancy, may alleviate some of the psychological problems faced by surrogates.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the Wellcome Trust [097857/Z/11/Z] and Nehru Trust, Cambridge. K.K. is the Medical Director of Corion Fertility Clinic. All other authors have no conflict of interest to declare.
      PubDate: Fri, 23 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey048
      Issue No: Vol. 33, No. 4 (2018)
  • Obesity associated advanced glycation end products within the human
           uterine cavity adversely impact endometrial function and embryo
           implantation competence
    • Authors: Antoniotti G; Coughlan M, Salamonsen L, et al.
      Pages: 654 - 665
      Abstract: STUDY QUESTIONDo obese levels of advanced glycation end products (AGEs) within the uterine cavity detrimentally alter tissue function in embryo implantation and placental development'SUMMARY ANSWERObese levels of AGEs activate inflammatory signaling (p65 NFκB) within endometrial epithelial cells and alter their function, cause endoplasmic reticulum (ER) stress in endometrial stromal cells and impair decidualization, compromise implantation of blastocyst mimics and inhibit trophoblast invasion.WHAT IS KNOWN ALREADYObese women experience a higher incidence of infertility, recurrent miscarriage and pregnancy complications compared with lean women. Oocyte donation cycles suggest a detrimental uterine environment plays a role in these outcomes.STUDY DESIGN, SIZE, DURATIONUterine lavage and tissues from lean (BMI 19.5–24.9, n = 17) and obese (BMI > 30, n = 16) women examined. Cell culture experiments utilizing human endometrial epithelial, trophectoderm and trophoblast cell lines and primary human stromal cells used to examine the functional impact of obese levels of AGEs.PARTICIPANTS/MATERIALS, SETTING, METHODSLevels of AGEs examined within uterine lavage assessed by ELISA to determine differences between lean and obese women. Expression and localization of AGEs, receptor for AGEs (RAGE) and NFκB within endometrial tissues obtained from lean and obese women determined by immunohistochemistry. Endometrial epithelial cells (ECC-1), primary human stromal cells and trophoblast cells (HTR8-SVneo) treated with lean (2000 nmol/mol lysine) or obese (8000 nmol/mol lysine) uterine levels of AGEs and p65 NFκB (western immunoblot), real-time adhesion, proliferation migration and invasion (xCelligence real-time cell function analysis), decidualization (cell morphology and prolactin release), ER stress (western immunoblot for p-PERK) determined. Co-cultures of endometrial epithelial cells and blastocyst mimics (trophectoderm spheroids) similarly treated with lean or obese uterine levels of AGEs to determine their impact on embryo implantation.MAIN RESULTS AND THE ROLE OF CHANCEAGEs were significantly elevated (P = 0.004) within the obese (6503.59 μmol/mol lysine) versus lean (2165.88 μmol/mol lysine) uterine cavity (uterine lavage) with increased immunostaining for AGEs, RAGE and NFkB within obese endometrial tissues during the proliferative phase of the menstrual cycle. Obese uterine levels of AGEs inhibited adhesion and proliferation of endometrial epithelial (ECC-1) cells compared to treatment with lean uterine levels of AGEs. Obese uterine AGE levels impacted primary human endometrial stromal cell decidualization and activated ER stress within these cells. Obese uterine levels of AGEs also inhibited trophectodermal spheroid adhesion to hormonally primed endometrial epithelial cells and trophoblast cell line HTR8/SV-neo invasion.LARGE SCALE DATAN/A.LIMITATIONS REASONS FOR CAUTIONMechanistic studies are performed in vitro and may not completely recapitulate cell function in vivo.WIDER IMPLICATIONS OF THE FINDINGSThese data corroborate clinical data suggesting the presence of an altered uterine environment in obese women and demonstrate that elevated uterine levels of AGEs within these women may detrimentally impact endometrial function, embryo implantation and placental development. Uterine AGE assessment in infertility work up may prove useful in determining underlying causes of infertility. AGEs can be targeted pharmacologically and such treatments may prove effective in improving reproductive complications experience by obese women.STUDY FUNDING/COMPETING INTEREST(S)Supported by NHMRC Fellowship (#1002028 to L.A.S.), and the Victorian Government’s Operational Infrastructure Support Program. MTC is supported by a JDRF Australia Clinical Research Network Career Development Award. The authors have declared that no conflict of interest exists.
      PubDate: Tue, 20 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey029
      Issue No: Vol. 33, No. 4 (2018)
  • Granulosa cells from human primordial and primary follicles show
           differential global gene expression profiles
    • Authors: Ernst E; Franks S, Hardy K, et al.
      Pages: 666 - 679
      Abstract: STUDY QUESTIONCan novel genetic candidates involved in follicle dormancy, activation and integrity be identified from transcriptomic profiles of isolated granulosa cells from human primordial and primary follicles'SUMMARY ANSWERThe granulosa cell compartment of the human primordial and primary follicle was extensively enriched in signal transducer and activator of transcription 3 (STAT3) and cAMP-response element binding protein (CREB) signalling, and several other putative signalling pathways that may also be mediators of follicle growth and development were identified.WHAT IS KNOWN ALREADYMechanistic target of rapamycin kinase (mTOR) signalling and the factors Forkhead Box L2 (FOXL2) and KIT proto-oncogene receptor tyrosine kinase (KITL) may be involved in defining the early steps of mammalian follicular recruitment through complex bidirectional signalling between the oocyte and granulosa cells. cAMP/protein kinase K (PKA)/CREB signalling is a feature of FSH-induced regulation of granulosa cell steroidogenesis that is essential to normal human fertility.STUDY DESIGN, SIZE, DURATIONA class comparison study was carried out on primordial follicles (n = 539 follicles) and primary follicles (n = 261) follicles) donated by three women having ovarian tissue cryopreserved before chemotherapy.PARTICIPANTS/MATERIALS, SETTING, METHODSRNA samples from isolates of laser capture micro-dissected oocytes and follicles from the primordial and primary stage, respectively, were sequenced on the HiSeq Illumina platform. Data mapping, quality control, filtering, FPKM (fragments per kilobase of exon per million) normalization and comparisons were performed. The granulosa cell contribution in whole follicle isolates was extracted in silico. Modelling of complex biological systems was performed using Ingenuity Pathway Analysis (IPA). For validation of transcriptomic findings, we performed quantitative RT-PCR of selected candidate genes. Furthermore, we interrogated the in situ localization of selected corresponding proteins using immunofluorescence.MAIN RESULTS AND THE ROLE OF CHANCEOur differentially expressed gene analysis revealed a number of transcripts in the granulosa cells to be significantly down- (736 genes) or up- (294 genes) regulated during the human primordial-to-primary follicle transition. The IPA analysis revealed enriched canonical signalling pathways not previously associated with granulosa cells from human primordial and primary follicles. Immunofluorescent staining of human ovarian tissue explored the intra-ovarian localization of FOG2, and FOXL2, which revealed the presence of forkhead box L2 (FOXL2) in both oocytes and granulosa cells in primary follicles, with a more enriched staining in the granulosa cells in primary follicles. Friend of GATA 2 (FOG2) stained strongly in oocytes in primordial follicles, with a shift towards granulosa cell as follicle stage advanced.LARGE SCALE DATA REASONS FOR CAUTIONThis is a descriptive study, and no functional assays were employed. The study was based on a limited number of patients, and it is acknowledged that natural biological variance exists in human samples. Strict filters were applied to accommodate the in silico extraction of the granulosa cell contribution. In support of this, quantitative RT-PCR was used to confirm selected candidate genes, and immunofluorescent staining was employed to interrogate the intra-ovarian distribution of selected corresponding proteins. Moreover, it is unknown whether the primordial follicles analysed represent those still in the resting pool, or those from the cohort that have entered the growing pool.WIDER IMPLICATIONS OF THE FINDINGSWe present, for the first time, a detailed description of global gene activity in the human granulosa cell compartment of primordial and primary follicles. These results may be utilized in the development of novel clinical treatment strategies aimed at improving granulosa cell function.STUDY FUNDING/COMPETING INTEREST(S)E.H.E. was supported by the Health Faculty, Aarhus University and Kong Christian Den Tiendes Fond. K.L.H. was supported by a grant from Fondens til Lægevidenskabens Fremme and Kong Christian Den Tiendes Fond. No authors have competing interests to declare.
      PubDate: Thu, 01 Mar 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey011
      Issue No: Vol. 33, No. 4 (2018)
  • Changes in keratin 8/18 expression in human granulosa cell lineage are
           associated to cell death/survival events: potential implications for the
           maintenance of the ovarian reserve
    • Authors: Gaytan F; Morales C, Roa J, et al.
      Pages: 680 - 689
      Abstract: STUDY QUESTIONIs keratin 8/18 (K8/K18) expression linked to cell death/survival events in the human granulosa cell lineage'SUMMARY ANSWERA close association exists between changes in K8/K18 expression and cell death/survival events along the human granulosa cell lineage lifespan.WHAT IS KNOWN ALREADYIn addition to their structural and mechanical functions, K8/K18 play essential roles regulating cell death, survival and differentiation in several non-gonadal epithelial tissues. Transfection of the granulosa-like tumor KGN cells with siRNA to interfere KRT8 and KRT18 expression increases FAS-mediated apoptosis, while an inverse association between K8/K18 expression and cell death has been found in the bovine antral follicles and corpus luteum. Yet, only fragmentary and inconclusive information exists regarding K8/K18 expression in the human ovary.STUDY DESIGN, SIZE, DURATIONExpression of K8/K18 was assessed by immunohistochemistry at different stages of the granulosa cell lineage, from flattened granulosa cells in primordial follicles to fully luteinized granulosa-lutein cells in the corpus luteum (including corpus luteum of pregnancy).PARTICIPANTS/MATERIALS, SETTING, METHODSImmunohistochemical detection of K8/K18 was conducted in 40 archival ovarian samples from women aged 17–39 years. K8/K18 expression was analyzed at the different stages of follicle development and corpus luteum lifespan. The proportions of primordial follicles showing all K8/K18-positive, all K8/K18 negative, or a mixture of K8/K18 negative and positive granulosa cells were quantified in 18 ovaries, divided into three age groups: ≤ 25 years (N = 6), 26–30 (N = 6) and 31–36 (N = 6) years. A total number of 1793 primordial, 750 transitional and 140 primary follicles were scored.MAIN RESULTS AND THE ROLE OF CHANCEA close association was found between changes in K8/K18 expression and cell death/cell survival events in the human granulosa cell lineage. Large secondary and early antral follicles (most of them undergoing atresia) and regressing corpora lutea displayed low/absent K8/K18 expression. Conversely, early growing and some large antral follicles, functional menstrual corpora lutea, as well as life-extended corpus luteum of pregnancy, in which cell death was scarce, showed high K8/K18 expression. Three sub-populations of primordial follicles were observed with respect to the presence of K8/K18 in their flattened granulosa cells, ranging from primordial follicles showing only positive granulosa cells [P0(+)], to others with a mixture of positive and negative cells [P0(+/−)] or follicles with only negative cells [P0(−)]. Significant age-related changes were found in the proportions of the different primordial follicle types. In relation to age, a positive correlation was found for P0(+) primordial follicles (R2= 0.7883, N = 18; P < 0.001), while negative correlations were found for P0(+/−) (R2 = 0.6853, N = 18; P < 0.001) and P0(−) (R2 = 0.6725, N = 18; P < 0.001) follicles. Furthermore, an age-related shift towards greater keratin expression was found in P0(+/−) follicles (χ2 = 19.07, P < 0.05).LARGE SCALE DATAN/A.LIMITATIONS REASONS FOR CAUTIONThis is a descriptive study. Hence, a cause-and-effect relationship between K8/K18 expression and cell death/survival cannot be directly established.WIDER IMPLICATIONS OF THE FINDINGSThis study describes, for the first time, the existence of sub-populations of primordial follicles on the basis of K8/K18 expression in granulosa cells, and that their proportions change with age. While a progressive increase in K8/K18 expression cannot be ruled out, our data are consistent with the hypothesis that primordial follicles expressing low levels of K8/K18 are preferentially ablated by follicle attrition, while primordial follicles showing high K8/K18 levels are those predominantly recruited into the growing pool. This suggests that K8/K18 expression could constitute a novel factor regulating primordial follicle death/survival, and raises the possibility that alterations of K8/K18 expression could be involved in the accelerated depletion of the ovarian reserve leading to premature ovarian insufficiency.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by Grants BFU2011-025021 and BFU2014-57581-P (Ministerio de Economía y Competitividad, Spain; co-funded with EU funds from FEDER Program); project PIE14-00005 (Flexi-Met, Instituto de Salud Carlos III, Ministerio de Sanidad, Spain); Projects P08-CVI-03788 and P12-FQM-01943 (Junta de Andalucía, Spain); and EU research contract DEER FP7-ENV-2007-1. CIBER Fisiopatología de la Obesidad y Nutrición is an initiative of Instituto de Salud Carlos III. The authors have nothing to disclose in relation to the contents of this study.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey010
      Issue No: Vol. 33, No. 4 (2018)
  • Impact of diet and bariatric surgery on anti-Müllerian hormone levels
    • Authors: Nilsson-Condori E; Hedenbro J, Thurin-Kjellberg A, et al.
      Pages: 690 - 693
      Abstract: STUDY QUESTIONDo serum levels of anti-Müllerian hormone (AMH) change in women of reproductive age following dietary and surgery-induced weight loss'SUMMARY ANSWERAMH levels increased after very low-calorie diet (VLCD) before surgery and decreased at 6 and 12 months after Roux-en-Y gastric bypass (RYGB), beyond expected normal age-related decline.WHAT IS KNOWN ALREADYObesity has negative effects on fertility and IVF outcomes, and possibly also on AMH levels. AMH correlates to the number of growing follicles and is used to predict the response to IVF treatment. However, AMH might decrease after bariatric surgery.STUDY DESIGN, SIZE, DURATIONA prospective cohort study of 48 women followed first for 8 weeks preoperatively, then operated with RYGB and followed postoperatively for 1 additional year.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen aged 18–35 years with a mean (SD) BMI 40.9 (3.6) kg/m2 were included at baseline (BL). After the VLCD, a RYGB was performed. Body weight and height were measured at BL and 1 year postoperatively. Hormones were analysed at BL, after VLCD on the day before surgery, and at 6 and 12 months postoperatively.MAIN RESULTS AND THE ROLE OF CHANCEMedian AMH levels were 30.0 pmol/L at BL and rose significantly after VLCD (median: 35.0 pmol/L; P = 0.014). Median AMH at 6 and 12 months postoperatively were significantly lower (19.5 and 18.0 pmol/L, respectively; P = 0.001). Free androgen index (FAI) was significantly lower after 12 months, compared to BL (1.2 vs 3.5, P < 0.0005).LIMITATIONS REASONS FOR CAUTIONUltrasound for PCOS diagnosis was not performed. The change in laboratory methods for AMH analysis during the study might be a limitation.WIDER IMPLICATIONS OF THE FINDINGSObese young women might choose bariatric surgery also for fertility reasons, and the observed decrease in FAI is in line with improved fertility. More research is needed to evaluate the clinical effects of the decrease of AMH, and the effect of bariatric surgery prior to IVF treatment.STUDY FUNDING/COMPETING INTEREST(S)Study-specific laboratory analyses were funded by the Swedish Regional Research Fund (ALF).
      Authors declare no competing interests.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Thu, 22 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey032
      Issue No: Vol. 33, No. 4 (2018)
  • Chronic hyperandrogenemia and western-style diet beginning at puberty
           reduces fertility and increases metabolic dysfunction during pregnancy in
           young adult, female macaques
    • Authors: Bishop C; Stouffer R, Takahashi D, et al.
      Pages: 694 - 705
      Abstract: STUDY QUESTIONWhat are the impacts of elevated testosterone (T) and an obesogenic western-style diet (WSD), either independently or together, on fertility and metabolic adaptations of pregnancy in primates'SUMMARY ANSWERTestosterone increases the time to achieve pregnancy, while a WSD reduces overall fertility, and the combination of testosterone and WSD additionally impairs glucose tolerance and causes pregnancy loss.WHAT IS KNOWN ALREADYBoth hyperandrogenemia and obesity are hallmarks of polycystic ovary syndrome, which is a leading cause of infertility among women worldwide. Female macaques receiving T and WSD beginning at puberty show increased metabolic, ovarian and uterine dysfunction in the non-pregnant state by 3 years of treatment.STUDY DESIGN, SIZE, DURATIONThe same cohort of female rhesus macaques continued treatments from the time of puberty (2.5 years) to 4 years, including this fertility trial. There were four groups (n = 9–10/group): controls (C), T-treated (T; average total serum level 1.35 ng/ml), WSD-treated, and combined T and WSD-treated (T + WSD) females.PARTICIPANTS/MATERIALS, SETTING, METHODSFemales, which were typically having menstrual cycles, were paired for 4 days with a proven male breeder following the late follicular rise in circulating estradiol (≥100 pg/ml). The presence of sperm in the reproductive tract was used to confirm mating. Animals went through up to three successive rounds of mating until they became pregnant, as confirmed by a rise in circulating mCG during the late luteal phase and ultrasound evidence of a gestational sac at Day 30 post-mating (GD30). Placental vascular parameters were also measured at GD30. Metabolic measurements consisted of fasting levels of blood glucose and insulin at approximately GD30, 60, 90 and 115, as well as an intravenous (iv) glucose tolerance test (GTT) at GD115.MAIN RESULTS AND THE ROLE OF CHANCEWhile all animals in the C and T groups eventually became pregnant, T-treated females on average had a greater interval to achieve pregnancy (P < 0.05). However, only ~70% of animals in the WSD and T + WSD groups became pregnant (P < 0.004). One pregnancy in T + WSD group resulted in an anembryonic pregnancy which miscarried around GD60, while another T + WSD female conceived with a rare identical twin pregnancy which required cessation due to impending fetal loss at GD106. Thus, the number of viable fetuses was less in the T + WSD group, compared to C, T or WSD. Placental blood volume at GD30 was reduced in all treatments compared to the C group (P < 0.05). Maternal P4 levels were elevated in the WSD (P < 0.03) group and E2 levels were elevated in T + WSD animals (P < 0.05). An increase in serum A4 levels throughout gestation was observed in all groups (P < 0.03) except WSD (P = 0.3). All groups displayed increased insulin resistance with pregnancy, as measured from the ivGTT during pregnancy. However, only the T + WSD group had a significant increase in fasting glucose levels and glucose clearance during the GTT indicating a worsened glucose tolerance. WSD treatment decreased female fetuses third trimester weights, but there was an interaction between WSD and T to increase female fetal weight when normalized to maternal weight.LARGE SCALE DATAN/A.LIMITATIONS REASONS FOR CAUTIONThe small number of pregnancies in the WSD and T + WSD groups hampers the ability to make definitive conclusions on effects during gestation. Also, the high fertility rate in the controls indicates the cohort was at their breeding prime age, which may impair the ability to observe subtle fertility defects. The low number of fetuses used for male and female analysis requires additional studies.WIDER IMPLICATIONS OF THE FINDINGSThe current findings strongly suggest that both hyperandrogenemia and obesity have detrimental effects on fertility and gestation in primates, which may be directly relevant to women with polycystic ovary syndrome.STUDY FUNDING/COMPETING INTEREST(S)All ONPRC Cores and Units were supported by NIH Grant P51 OD011092 awarded to ONPRC. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH) under Award Number P50HD071836 (to R.L.S.). The authors have no competing conflict of interests to disclose.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey013
      Issue No: Vol. 33, No. 4 (2018)
  • The numbers of 2– 5 and 6–9 mm ovarian follicles are inversely
           correlated in both normal women and in polycystic ovary syndrome patients:
           what is the missing link'
    • Authors: Peigné M; Catteau-Jonard S, Robin G, et al.
      Pages: 706 - 714
      Abstract: STUDY QUESTIONIs the negative correlation between the numbers of 2–5 and 6–9 mm follicles influenced by ovarian and/or metabolic parameter(s) in young control women and in patients with polycystic ovarian syndrome (PCOS)'SUMMARY ANSWEROur study confirmed that the negative correlation between numbers of follicles sized 2–5 and 6–9 mm was stronger in PCOS than in young control women and was not linked to any ovarian or metabolic parameter.WHAT IS KNOWN ALREADYPrevious reports described a direct negative correlation between the number of small antral follicles (2–5 mm) and large antral follicle (6–9 mm) during the early follicular phase (cycle Days 2–5) in normal and PCOS women. Numerous factors, that could be either intrinsic to the ovary or secondary to metabolic influence and/or gonadotropin regulation, might account for this.STUDY DESIGN, SIZE, DURATIONSix hundred and thirty-nine patients with PCOS according to Rotterdam Criteria and 157 control women were recruited in this retrospective cross-sectional study from January 2009 to January 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSData were obtained from a database of clinical, hormonal and ultrasound (U/S) features recorded consecutively in a single reproductive medicine centre. Univariate correlations between the various parameters were analysed by the Spearman’s correlation test. All variables significantly related to the 2–5 and/or 6–9 mm follicle numbers were included in a principal component analysis (PCA) in order to structure the data and to obtain collections of uncorrelated variables, called principal components (PC), which are linear combinations of the original variables.MAIN RESULTS AND THE ROLE OF CHANCEBy univariate analysis, the 2–5 and 6–9 mm follicle numbers were strongly but negatively correlated in both populations. Many other variables were correlated to the 2–5 and/or 6–9 mm follicle numbers and to each other. By PCA, these relationships were gathered into four independent PCs in each population. In both groups, the 2–5 and 6–9 mm follicle numbers correlated strongly and inversely to a specific PC. Among the other variables tested, only serum oestradiol level correlated weakly to this PC in the control group. Two other uncorrelated PCs gathered relationships between variables linked to the metabolic status and the gonadotropin regulation both in control and PCOS women. Lastly, a fourth PC included relationships which linked to ovarian ageing in controls and to follicle dysregulation in patients with PCOS.LIMITATIONS, REASONS FOR CAUTIONOur controls did not represent the general population since they were recruited in an ART centre; we used a modified Rotterdam classification for PCOS using follicle count and/or serum AMH level with in-house thresholds to define the follicle excess; the AMH assay used is no longer commercially available.WIDER IMPLICATIONS OF THE FINDINGSFactor(s) regulating specifically the equilibrium between the 2–5 and 6–9 mm follicle numbers still need(s) to be identified. More attention should be paid to the oocyte.STUDY FUNDING/COMPETING INTEREST(S)None.
      PubDate: Wed, 07 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey017
      Issue No: Vol. 33, No. 4 (2018)
  • Fruit and vegetable consumption and risk of endometriosis
    • Authors: Harris H; Eke A, Chavarro J, et al.
      Pages: 715 - 727
      Abstract: STUDY QUESTIONIs there an association between intake of fruits and vegetables and risk of laparoscopically confirmed endometriosis'SUMMARY ANSWERHigher intake of fruits, particularly citrus fruits, is associated with a lower risk of endometriosis.WHAT IS KNOWN ALREADYTwo case–control studies have examined the associations between fruit and vegetable intake and endometriosis risk with contrasting results. Diets rich in fruits and vegetables include higher levels of pro-vitamin A nutrients (alpha-carotene, beta-carotene, beta-cryptoxanthin) and women with endometriosis have been reported to have lower intake of vitamin A than women without endometriosis.STUDY DESIGN SIZE, DURATIONA prospective cohort study using data collected from 70 835 premenopausal women from 1991 to 2013 as part of the Nurses’ Health Study II cohort.PARTICIPANTS/MATERIALS, SETTING, METHODSDiet was assessed with a validated food frequency questionnaire (FFQ) every 4 years. Cases were restricted to laparoscopically confirmed endometriosis. Cox proportional hazards models were used to calculate rate ratios (RR) and 95% CI.MAIN RESULTS AND THE ROLE OF CHANCEDuring 840 012 person-years of follow-up, 2609 incident cases of laparoscopically confirmed endometriosis were reported (incidence rate = 311 per 100 000 person-years). We observed a non-linear inverse association between higher fruit consumption and risk of laparoscopically confirmed endometriosis (Psignificance of the curve = 0.005). This inverse association was particularly evident for citrus fruits. Women consuming ≥1 servings of citrus fruits/day had a 22% lower endometriosis risk (95% CI = 0.69–0.89; Ptrend = 0.004) compared to those consuming <1 serving/week. No association was observed between total vegetable intake and endometriosis risk. However, women consuming ≥1 servings/day cruciferous vegetables had a 13% higher risk of endometriosis (95% CI = 0.95–1.34; Ptrend = 0.03) compared to those consuming <1 serving/week. Of the nutrients examined, only beta-cryptoxanthin intake was significantly associated with lower endometriosis risk (RR fifth quintile = 0.88; 95% CI = 0.78–1.00; Ptrend = 0.02).LIMITATIONS REASONS FOR CAUTIONSome error in the self-reporting of dietary intake is expected, however, use of a validated FFQ and examining diet prospectively across multiple time points, make it unlikely that this non-differential misclassification strongly influenced the results.WIDER IMPLICATIONS OF THE FINDINGSOur findings suggest that a higher intake of fruits, particularly citrus fruits, is associated with a lower risk of endometriosis, and beta-cryptoxanthin in these foods may partially explain this association. In contrast to what we hypothesized, consumption of some vegetables increased endometriosis risk which may indicate a role of gastrointestinal symptoms in both the presentation and exacerbation of endometriosis-related pain; however, it is not clear what components of these foods might underlie the observed associations. Future studies examining dietary patterns that consider different combinations of food intake may help clarify these associations.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by research grants HD4854, HD52473 and HD57210 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and grant P30 DK046200 from the National Institute of Diabetes and Digestive and Kidney Diseases. The Nurses’ Health Study II is supported by the Public Health Service grant UM1 CA176726 from the National Cancer Institute, National Institutes of Health. HRH is supported by the National Cancer Institute, National Institutes of Health (K22 CA193860). No competing interests.TRIAL REGISTRATION NUMBERn/a.
      PubDate: Thu, 01 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey014
      Issue No: Vol. 33, No. 4 (2018)
  • Biomarkers of preconception stress and the incidence of pregnancy loss
    • Authors: Lynch C; Sundaram R, Buck Louis G.
      Pages: 728 - 735
      Abstract: STUDY QUESTIONAre biomarkers of preconception stress associated with pregnancy loss'SUMMARY ANSWERPreconception stress, as measured by basal salivary cortisol and alpha-amylase concentrations, is not associated with pregnancy loss.WHAT IS KNOWN ALREADYMany studies, most of which have been retrospective, have identified an association between stressful life events and perceived stress and miscarriage.STUDY DESIGN, SIZE, DURATIONA prospective pregnancy study with preconception enrollment was conducted between 2005 and 2009. Among the 344 women who became pregnant during the Longitudinal Investigation of Fertility and the Environment (LIFE) study, 337 (98%) had salivary biomarker data for analysis.PARTICIPANTS/MATERIALS, SETTING, METHODSCouples planning pregnancy were followed for up to 12 months as they tried to become pregnant and through pregnancy if it occurred. Participating women collected a basal saliva sample on the morning following enrollment and a second on the morning following their next menses to measure cortisol and alpha-amylase, biomarkers of stress. Women used home pregnancy tests on the day of expected menses. A pregnancy loss was defined as a negative pregnancy test following a positive pregnancy test, the onset of menses, or for pregnancies that survived to clinical recognition, recognition of the loss by a healthcare provider.MAIN RESULTS AND THE ROLE OF CHANCEAmong the 337 couples, the median age of female and male partners was 29 and 31 years, respectively. Most of the women were non-Hispanic white (83%) and highly educated. There were 97 pregnancy losses reported among the 337 pregnancies. The median gestational age at loss was 6 weeks 5 days with only two losses occurring in the second trimester. Using Cox proportional hazards models, we found no clear pattern of association between two preconceptional biomarkers of stress (salivary cortisol and alpha-amylase concentrations) modeled both continuously or in tertiles and incident pregnancy loss after adjustment for confounders.LIMITATIONS REASONS FOR CAUTIONOur prior work suggests that women enrolled in the LIFE Study had lower stress levels than women in the general population. Owing to concerns regarding participant burden, we were unable to collect serial saliva measurements, which would have allowed us to examine the association between stress in early pregnancy and pregnancy loss. Further, with regard to the measurement of perceived stress, the Cohen’s Perceived Stress Scale was only administered at baseline. While every attempt was made to ensure diversity in the cohort, non-Hispanic white women were over-represented, therefore it is possible that the results might not be generalizable to all women.WIDER IMPLICATIONS OF THE FINDINGSIn one of the largest studies in the USA to prospectively capture data on the incidence of early pregnancy loss, we found no clear association between two biomarkers of preconception stress (measured in saliva) and pregnancy loss.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3–3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Tue, 27 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey030
      Issue No: Vol. 33, No. 4 (2018)
  • Parity associated with telomere length among US reproductive age women
    • Authors: Pollack A; Rivers K, Ahrens K.
      Pages: 736 - 744
      Abstract: STUDY QUESTIONIs telomere length related to parity among a nationally representative sample of US reproductive age women'SUMMARY ANSWERHistory of live birth was associated with shorter telomere length.WHAT IS KNOWN ALREADYShorter telomeres have been linked with a range of chronic health conditions and mortality and parity has been associated with health indicators. However, there is a lack of research on how parity relates to telomere length.STUDY DESIGN, SIZE, DURATIONThis nationally representative, cross-sectional study included 1954 women from the National Health and Nutrition Examination Survey, 1999–2002, the only survey period which includes measurement of telomere length.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen aged 20–44 were included. Parity, defined as number of previous live births, was ascertained by questionnaire. Leukocyte telomere length was measured by polymerase chain reaction and reported as a ratio in relation to standard reference DNA (T/S ratio). The relationship between leukocyte T/S ratio and parity was examined using survey weighted linear regression. Models were adjusted for race/ethnicity, age, BMI, income-to-poverty ratio, education, early age at menarche and smoking status.MAIN RESULTS AND THE ROLE OF CHANCEAmong reproductive age women in the US, the adjusted mean leukocyte T/S ratio was 4.2% (95% CI: 0.9, 7.3) shorter in parous compared with nulliparous women. Parity was associated with 116 fewer base pairs (95% CI: 26, 204) on average, using estimated coefficients from the adjusted linear regression models and mean covariate values.LIMITATIONS REASONS FOR CAUTIONThis study was cross-sectional and therefore was unable to establish temporality. The dataset lacked information on social factors, stress and fertility status, which may help explain these findings. Only two previous studies have examined this question and our findings should be interpreted with caution.WIDER IMPLICATIONS OF THE FINDINGSThese findings in a nationally representative sample of US reproductive age women suggest that history of live birth may be associated with accelerated cellular aging. The magnitude of the observed association was greater than that of the impact of smoking or obesity on telomere length, suggesting that parity may have an independent influence on cellular aging and warrant further study.STUDY FUNDING/COMPETING INTEREST(S)The study was funded in part by the Undergraduate Research Scholars Program at George Mason University. The authors have no conflicts of interest.TRIAL REGISTRATION NUMBERNA.
      PubDate: Wed, 14 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey024
      Issue No: Vol. 33, No. 4 (2018)
  • Origin and composition of cell-free DNA in spent medium from human embryo
           culture during preimplantation development
    • Authors: Vera-Rodriguez M; Diez-Juan A, Jimenez-Almazan J, et al.
      Pages: 745 - 756
      Abstract: STUDY QUESTIONWhat is the origin and composition of cell-free DNA in human embryo spent culture media'SUMMARY ANSWERCell-free DNA from human embryo spent culture media represents a mix of maternal and embryonic DNA, and the mixture can be more complex for mosaic embryos.WHAT IS KNOWN ALREADYIn 2016, ~300 000 human embryos were chromosomally and/or genetically analyzed using preimplantation genetic testing for aneuploidies (PGT-A) or monogenic disorders (PGT-M) before transfer into the uterus. While progress in genetic techniques has enabled analysis of the full karyotype in a single cell with high sensitivity and specificity, these approaches still require an embryo biopsy. Thus, non-invasive techniques are sought as an alternative.STUDY DESIGN, SIZE, DURATIONThis study was based on a total of 113 human embryos undergoing trophectoderm biopsy as part of PGT-A analysis. For each embryo, the spent culture media used between Day 3 and Day 5 of development were collected for cell-free DNA analysis. In addition to the 113 spent culture media samples, 28 media drops without embryo contact were cultured in parallel under the same conditions to use as controls. In total, 141 media samples were collected and divided into two groups: one for direct DNA quantification (53 spent culture media and 17 controls), the other for whole-genome amplification (60 spent culture media and 11 controls) and subsequent quantification. Some samples with amplified DNA (N = 56) were used for aneuploidy testing by next-generation sequencing; of those, 35 samples underwent single-nucleotide polymorphism (SNP) sequencing to detect maternal contamination. Finally, from the 35 spent culture media analyzed by SNP sequencing, 12 whole blastocysts were analyzed by fluorescence in situ hybridization (FISH) to determine the level of mosaicism in each embryo, as a possible origin for discordance between sample types.PARTICIPANTS/MATERIALS, SETTING, METHODSTrophectoderm biopsies and culture media samples (20 μl) underwent whole-genome amplification, then libraries were generated and sequenced for an aneuploidy study. For SNP sequencing, triads including trophectoderm DNA, cell-free DNA, and follicular fluid DNA were analyzed. In total, 124 SNPs were included with 90 SNPs distributed among all autosomes and 34 SNPs located on chromosome Y. Finally, 12 whole blastocysts were fixed and individual cells were analyzed by FISH using telomeric/centromeric probes for the affected chromosomes.MAIN RESULTS AND THE ROLE OF CHANCEWe found a higher quantity of cell-free DNA in spent culture media co-cultured with embryos versus control media samples (P ≤ 0.001). The presence of cell-free DNA in the spent culture media enabled a chromosomal diagnosis, although results differed from those of trophectoderm biopsy analysis in most cases (67%). Discordant results were mainly attributable to a high percentage of maternal DNA in the spent culture media, with a median percentage of embryonic DNA estimated at 8%. Finally, from the discordant cases, 91.7% of whole blastocysts analyzed by FISH were mosaic and 75% of the analyzed chromosomes were concordant with the trophectoderm DNA diagnosis instead of the cell-free DNA result.LIMITATIONS, REASONS FOR CAUTIONThis study was limited by the sample size and the number of cells analyzed by FISH.WIDER IMPLICATIONS OF THE FINDINGSThis is the first study to combine chromosomal analysis of cell-free DNA, SNP sequencing to identify maternal contamination, and whole-blastocyst analysis for detecting mosaicism. Our results provide a better understanding of the origin of cell-free DNA in spent culture media, offering an important step toward developing future non-invasive karyotyping that must rely on the specific identification of DNA released from human embryos.STUDY FUNDING/ COMPETING INTERESTThis work was funded by Igenomix S.L. There are no competing interests.
      PubDate: Tue, 20 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey028
      Issue No: Vol. 33, No. 4 (2018)
  • Analysis of segregation patterns of quadrivalent structures and the effect
           on genome stability during meiosis in reciprocal translocation carriers
    • Authors: Zhang S; Lei C, Wu J, et al.
      Pages: 757 - 767
      Abstract: STUDY QUESTIONDo specific factors affect the segregation patterns of a quadrivalent structure and can the quadrivalent affect genome stability during meiosis'SUMMARY ANSWERMeiotic segregation patterns can be affected by the carrier’s gender and age, location of breakpoints and chromosome type, and the quadrivalent structure can increase genome instability during meiosis.WHAT IS KNOWN ALREADYCarriers of reciprocal translocations have an increased genetic reproductive risk owing to the complex segregation patterns of a quadrivalent structure. However, the results of previous studies on the factors that affect segregation patterns seem to be contradictory, and the effect of a quadrivalent on genome stability during meiosis is unknown.STUDY DESIGN, SIZE, DURATIONWe designed a retrospective study to analyze the segregation patterns of 24 chromosomes from reciprocal translocation and non-translocation patients. Data for 356 reciprocal translocation carriers and 53 patients with the risk to transmit monogenic inherited disorders (RTMIDs) undergoing PGD-single nucleotide polymorphism array analysis were collected. The study was performed between March 2014 and July 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSSegregation patterns of a quadrivalent in 1842 blastocysts from 466 assisted reproduction cycles of reciprocal translocation carriers were analyzed according to the location of chromosome breakpoints, the carrier’s gender and age, and chromosome type. In addition, to analyze the effect of quadrivalent structure on genome stability, segregation products of chromosomes which are not involved in the translocation from translocation carriers were compared with those of 23 pairs of chromosomes in 318 blastocysts from 72 assisted reproduction cycles of patients with RTMIDs.MAIN RESULTS AND THE ROLE OF CHANCEThe percentage of adjacent-2 products with severe asymmetric quadrivalent was significantly higher than those with mild asymmetric quadrivalent (P = 0.020) while, in contrast, the incidence of 4:0/others was lower (P = 0.030). The frequencies of adjacent-1, adjacent-2 and 3:1 products differed between male and female carriers (P < 0.001, P = 0.015 and P = 0.001, respectively), and also for adjacent-1 and 4:0/others products in young versus older carriers (P = 0.04 and P = 0.002, respectively). In addition, adjacent-1 products of a quadrivalent with an acrocentric chromosome were significantly higher than those of a quadrivalent without an acrocentric chromosome (P = 0.001). Moreover, a quadrivalent could significantly increase the frequencies of abnormal chromosomes compared to patients with RTMIDs (P = 0.048, odds ratio (OR) = 1.43, 95% CI = 1.01–2.43), especially for the male carriers (P = 0.018, OR = 1.58, 95% CI = 1.08–2.25). In contrast, for older carriers, no difference was found in both aneuploidy and segmental anomalies compared to patients with RTMIDs.LIMITATIONS, REASONS FOR CAUTIONThe study contained appropriate controls, yet the analysis was limited by a small number of control patients and embryos.WIDER IMPLICATIONS OF THE FINDINGSUntil now, there had been no definite report about the effect of quadrivalents on genome stability in reciprocal translocation carriers compared with control samples, and in the present study the large sample size ensured a detailed analysis of factors with a possible impact on segregation patterns. These data provide a better insight into the meiotic mechanisms involved in non-disjunction events in gametes from reciprocal translocation carriers. In addition, our results will help to provide each reciprocal translocation carrier couple undergoing PGD with more appropriate genetic counseling and a better understanding of the large numbers of abnormal embryos with chromosome aneuploidy.STUDY FUNDING/COMPETING INTEREST(S)The research was supported by the Research Funding of Shanghai Ji Ai Genetics & IVF Institute and the authors declare a lack of competing interests in this study.
      PubDate: Fri, 23 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey036
      Issue No: Vol. 33, No. 4 (2018)
  • Corrigendum: Induced abortion
    • Authors: .
      Pages: 768 - 768
      PubDate: Mon, 26 Feb 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey042
      Issue No: Vol. 33, No. 4 (2018)
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