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Publisher: Oxford University Press   (Total: 370 journals)

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Showing 1 - 200 of 370 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 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: 56, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 82, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 15, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 128, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 41, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 156, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 18, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 15)
American J. of Legal History     Full-text available via subscription   (Followers: 4, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 26, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 24)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 26, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 47, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 19, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 51, 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: 21)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 12)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 27, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 47, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 236, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 19, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 28, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 138, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 65, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 61, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 45, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 33, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 510, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 79, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 27)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 56, 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: 10, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal  
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 11, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 39, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 16, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 21, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 8, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 17, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 58, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 24, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 7, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 25)
Current Zoology     Full-text available via subscription   (SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 12)
Diplomatic History     Hybrid Journal   (Followers: 18, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 14, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 54, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 46, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 13, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 25, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 10, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 15, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 47, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, 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: 8, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 8, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 153, 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: 22, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 27, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 39, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 12, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 8, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 20, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 25, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 21, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 30, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 19, 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: 10, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 31, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 25, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 46, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 12, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 21, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 20, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 27, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 23, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 78, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 19, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 58, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 54, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 9)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 2, 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: 8, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 29, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 4, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 51, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 27)
Intl. Health     Hybrid Journal   (Followers: 4, 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: 32, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 59, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 127, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 3, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 28, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 8, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 32, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 13, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 29, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 17, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 36, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 17, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 39, 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: 17, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 16, 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: 34, 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: 12, 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: 15, 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: 34, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 23, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 19)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 21, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 2)
J. of Heredity     Hybrid Journal   (Followers: 3, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 20, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 40, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 9, SJR: 0.388, h-index: 31)

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Journal Cover Human Reproduction
  [SJR: 2.271]   [H-I: 179]   [78 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0268-1161 - ISSN (Online) 1460-2350
   Published by Oxford University Press Homepage  [370 journals]
  • Mass spectrometry, immunoassay and valid steroid measurements in
           reproductive medicine and science
    • Authors: Handelsman DJ.
      First page: 1147
      Abstract: testosteronemass spectrometryimmunoassaysteroid assayvalidity
      PubDate: 2017-04-27
      DOI: 10.1093/humrep/dex078
  • On the appropriate interpretation of evidence: the example of culture
           media and birth weight
    • Authors: Roberts SA; Vail A.
      First page: 1151
      PubDate: 2017-04-19
      DOI: 10.1093/humrep/dex081
  • Developments in IVF warrant the adoption of new performance indicators for
           ART clinics, but do not justify the abandonment of patient-centred
    • Authors: Wilkinson JJ; Roberts SA, Vail AA.
      First page: 1155
      Abstract: Recent advances in embryo freezing technology together with growing concerns over multiple births have shifted the paradigm of appropriate IVF. This has led to the adoption of new performance indicators for ART clinics by national reporting schemes, such as those curated by the Society for Assisted Reproductive Technology (SART) and the Human Fertilization and Embryology Authority (HFEA). Using these organizations as case studies, we review several outcome measures from a statistical perspective. We describe several denominators that are used to calculate live birth rates. These include cumulative birth rates calculated from all fresh and frozen transfer procedures arising from a particular egg collection or cycle initiation, and live birth rates calculated per embryo transferred. Using data from both schemes, we argue that all cycles should be included in the denominator, regardless of whether or not egg collection and fertilization were successful. Excluding cancelled cycles reduces the impact of confounding due to patient characteristics but also removes policy and performance differences which we argue represent relevant sources of variation. It may be misleading to present prospective patients with essentially hypothetical measures of performance predicated on parity of ovarian stimulation and transfer policies. Although live birth per embryo has the advantage of encouraging single embryo transfer, we argue that it is prone to misinterpretation. This is because the likelihood of live birth is not proportional to the number of embryos transferred. We conclude that it is not possible to present a single measure that encompasses both effectiveness and safety. Instead, we propose that a set of clear, relevant outcome indicators is necessary to enable subfertile patients to make informed choices regarding whether and where to be treated.
      PubDate: 2017-03-24
      DOI: 10.1093/humrep/dex063
  • Induced abortion
    • Authors: .
      First page: 1160
      Abstract: Abortion is common. Data on abortion rates are inexact but can be used to explore trends. Globally, the estimated rate in the period 2010–2014 was 35 abortions per 1000 women (aged 15–44 years), five points less than the rate of 40 for the period 1990–1994. Abortion laws vary around the world but are generally more restrictive in developing countries. Restrictive laws do not necessarily deter women from seeking abortion but often lead to unsafe practice with significant mortality and morbidity. While a legal framework for abortion is a prerequisite for availability, many laws, which are not evidence based, restrict availability and delay access. Abortion should be available in the interests of public health and any legal framework should be as permissive as possible in order to promote access. In the absence of legal access, harm reduction strategies are needed to reduce abortion-related mortality and morbidity. Abortion can be performed surgically (in the first trimester, by manual or electric vacuum aspiration) or with medication: both are safe and effective. Cervical priming facilitates surgery and reduces the risk of incomplete abortion. Diagnosis of incomplete abortion should be made on clinical grounds, not by ultrasound. Septic abortion is a common cause of maternal death almost always following unsafe abortion and thus largely preventable. While routine follow-up after abortion is unnecessary, all women should be offered a contraceptive method immediately after the abortion. This, together with improved education and other interventions, may succeed in reducing unintended pregnancy.
      PubDate: 2017-04-10
      DOI: 10.1093/humrep/dex071
  • Revisiting the human seminiferous epithelium cycle
    • Authors: Nihi FF; Gomes MM, Carvalho FR, et al.
      First page: 1170
      Abstract: STUDY QUESTIONCan all types of testicular germ cells be accurately identified by microscopy techniques and unambiguously distributed in stages of the human seminiferous epithelium cycle (SEC)?SUMMARY ANSWERBy using a high-resolution light microscopy (HRLM) method, which enables an improved visualization of germ cell morphological features, we identified all testicular germ cells in the seminiferous epithelium and precisely grouped them in six well-delimitated SEC stages, thus providing a reliable reference source for staging in man.WHAT IS ALREADY KNOWNMorphological characterization of germ cells in human has been done decades ago with the use of conventional histological methods (formaldehyde-based fixative -Zenker-formal- and paraffin embedding). These early studies proposed a classification of the SEC in six stages. However, the use of stages as baseline for morphofunctional evaluations of testicular parenchyma has been difficult because of incomplete morphological identification of germ cells and their random distribution in the human SEC.STUDY DESIGN, SIZE, DURATIONTesticular tissue from adult and elderly donors with normal spermatogenesis according to Levin's, Johnsen's and Bergmann's scores were used to evaluate germ cell morphology and validate their distribution and frequency in stages throughout human spermatogenesis.PARTICIPANTS/MATERIALS, SETTING, METHODSTesticular tissue from patients diagnosed with congenital bilateral agenesis of vas deferens (n = 3 adults) or prostate cancer (n = 3 elderly) were fixed in glutaraldehyde and embedded in araldite epoxy resin. Morphological analyses were performed by both light and transmission electron microscopy.MAIN RESULTS AND THE ROLE OF CHANCEHRLM method enabled a reliable morphological identification of all germ cells (spermatogonia, spermatocytes and spermatids) based on high-resolution aspects of euchromatin, heterochromatin and nucleolus. Moreover, acrosomal development of spermatids was clearly revealed. Altogether, our data redefined the limits of each stage leading to a more reliable determination of the SEC in man.LIMITATIONS, REASONS FOR CAUTIONOccasionally, germ cells can be absent in some tubular sections. In this situation, it has to be taken into account the germ cell association proposed in the present study to classify the stages.WIDER IMPLICATIONS OF THE FINDINGSOur findings bring a new focus on the morphology and development of germ cells during the SEC in human. Application of HRLM may be a valuable tool for research studies and clinical andrology helping to understand some testicular diseases and infertility conditions which remain unsolved.STUDY FUNDING/COMPETING INTERESTExperiments were partially supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The authors declare that there are no conflicts of interest.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: 2017-03-28
      DOI: 10.1093/humrep/dex064
  • Sex chromosome-dependent differential viability of human spermatozoa
           during prolonged incubation
    • Authors: You Y; Kwon W, Saidur Rahman M, et al.
      First page: 1183
      Abstract: STUDY QUESTIONAre there significant differences in the ability of X chromosome-bearing (X) spermatozoa and Y chromosome-bearing (Y) spermatozoa to survive incubation under stressful conditions?SUMMARY ANSWERY spermatozoa are more vulnerable to stress than their X counterparts depending on culture period and temperature, and show higher expression of apoptotic proteins.WHAT IS KNOWN ALREADYThe primary sex ratio is determined by there being an equal number of spermatozoa carrying X and Y chromosomes. This balance can be skewed by exposure to stressful environmental conditions such as changes in pH, pollutants or endocrine disruptors. However, less is known about the ability of sperm carrying either sex chromosome to withstand environmental stress.STUDY DESIGN, SIZE, DURATIONThe difference in survival between X and Y spermatozoa was evaluated by measuring motility, viability and Y:X chromosome ratio during incubation for 5 days, at three temperatures (4, 22 and 37°C), and three pH conditions (6.5, 7.5 and 8.5). To identify the critical factors that determine the survival of X and Y bearing spermatozoa, we analysed the expression levels of apoptosis-related proteins (Bcl, Bax and Caspase-3), as well as the extent of DNA damage under a subset of conditions.PARTICIPANTS/MATERIALS, SETTING, METHODSSemen samples were obtained by masturbation from normozoospermic donors after 3 days of sexual abstinence. Four samples with >60% motility from different donors were mixed to obtain sufficient semen and eliminate sampling-related bias. Data are presented as mean ± SD of three independent experiments. Mean age of donors was 28.7 ± 3.2 years.MAIN RESULTS AND THE ROLE OF CHANCEIn total, 58 489 spermatozoa were scored. The viability of Y spermatozoa was lower after exposure to different temperatures and culture periods than that of X spermatozoa (P < 0.05). Increased expression of apoptotic proteins in live Y spermatozoa was observed, despite the addition of tocopherol to the culture medium (P < 0.05).LIMITATIONS, REASONS FOR CAUTIONSpermatozoa were cultured in vitro during the treatment period. It is difficult to extrapolate the observed lifespan differences to spermatozoa survival in vivo. The experiments were replicated only three times.WIDER IMPLICATIONS OF THE FINDINGSThe prolonged survival of X spermatozoa under stressful conditions might lead to shifts in the ratio of male-to-female births.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (no. NRF-2014R1A2A2A01002706). The authors declare no competing financial interests.
      PubDate: 2017-04-19
      DOI: 10.1093/humrep/dex080
  • Effect of cranial irradiation on sperm concentration of adult survivors of
           childhood acute lymphoblastic leukemia: a report from the St. Jude
           Lifetime Cohort Study †
    • Authors: Green DM; Zhu L, Wang M, et al.
      First page: 1192
      Abstract: STUDY QUESTIONDoes lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology?SUMMARY ANSWERCRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology.WHAT IS KNOWN ALREADYTreatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology.STUDY DESIGN, SIZE, DURATIONThis cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013.PARTICIPANTS/MATERIALS, SETTING, METHODSThe inclusion criteria were males, ≥18 years of age, ≥10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI.MAIN RESULTS AND THE ROLE OF CHANCECompared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20–26 Gy (P = 0.58). Participants 5–9 years of age at diagnosis compared to those 0–4 years of age (RR = 1.30, 95% CI, 1.05–.61) or those treated with 8–12 g/m2 CED (RR = 2.06, 95% CI, 1.08–3.94) or ≥12 g/m2 CED (RR = 2.12, 95% CI, 1.09–4.12) compared to those treated with >0 to <4 g/m2 CED had an increased risk for oligospermia or azoospermia.LIMITATIONS, REASONS FOR CAUTIONOur study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia.WIDER IMPLICATIONS OF THE FINDINGSTreatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/m2 and an age at diagnosis of 5–9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the National Institutes of Health (grant numbers CA 21765, CA 195547, CA00874) and the American Lebanese Syrian Associated Charities (ALSAC). The authors have no competing interests to declare.
      PubDate: 2017-04-21
      DOI: 10.1093/humrep/dex082
  • Single versus repeat doses of misoprostol for treatment of early pregnancy
           loss—a randomized clinical trial
    • Authors: Mizrachi Y; Dekalo A, Gluck O, et al.
      First page: 1202
      Abstract: STUDY QUESTIONDoes repeat administration of misoprostol for early pregnancy loss increase the treatment success rate?SUMMARY ANSWERRepeat administration of misoprostol does not increase the treatment success rate, and is associated with more analgesics use.WHAT IS KNOWN ALREADYMisoprostol reduces the need for surgical evacuation and shortens the time to complete expulsion in patients with early pregnancy loss. However, the impact of repeat doses of misoprostol is not clear.STUDY DESIGN, SIZE, DURATIONA randomized clinical trial was conducted in a single tertiary hospital, recruiting women with early pregnancy loss (<12 weeks), seeking medical treatment, between August 2015 and June 2016. A sample size of 160 patients was sufficient to detect a 30% decrease in treatment success.PARTICIPANTS/MATERIALS, SETTING, METHODSParticipants received 800 μg of misoprostol vaginally on Day 1, and were then randomly assigned into two groups: Patients in the single-dose group were evaluated on Day 8. Patients in the repeat-dose group were evaluated on Day 4, when they were given a repeat dose if required, and scheduled for re-evaluation on Day 8. If complete expulsion was not achieved on Day 8 (endometrial thickness >15 mm or the presence of gestational sac on transvaginal sonography), participants underwent surgical evacuation. The primary outcome was treatment success, defined as no need for surgical intervention up to Day 8.MAIN RESULTS AND THE ROLE OF CHANCEFinal analysis included 87 participants in the single-dose group and 84 participants in the repeat-dose group, out of whom 41 (48.8%) received a second dose. Treatment succeeded in 67 (77%) patients in the single-dose group and 64 (76%) patients in the repeat-dose group (RR 0.98; 95% CI 0.83–1.16; P = 0.89). Patients in the repeat-dose group reported more use of over the counter analgesics (82.1% versus 69.0%, P = 0.04).LIMITATIONS, REASONS FOR CAUTIONThe study was not blinded and our definition of complete expulsion may be debated. Follow-up time was not equal in all participants, since some had a complete expulsion on Day 4 and some underwent emergent D&C before Day 8. This, however, should not affect the primary outcome.WIDER IMPLICATIONS OF THE FINDINGSOur results suggest that a single-dose protocol is superior to a repeat-dose protocol due to a comparable success rate and more favorable outcomes regarding the need for analgesic drugs.STUDY FUNDING/COMPETING INTEREST(S)We did not receive funding for this study and we declare no conflict of interest.TRIAL REGISTRATION (NCT02515604).TRIAL REGISTRATION DATE2 August 2015.DATE OF FIRST PATIENT'S ENROLMENT19 August 2015.
      PubDate: 2017-04-10
      DOI: 10.1093/humrep/dex074
  • Extravillous trophoblast invasion of venous as well as lymphatic vessels
           is altered in idiopathic, recurrent, spontaneous abortions
    • Authors: Windsperger K; Dekan S, Pils S, et al.
      First page: 1208
      Abstract: STUDY QUESTIONDo extravillous trophoblasts (EVTs) invade non-arterial decidual vessels in healthy and pathological pregnancies?SUMMARY ANSWEROur results reveal that trophoblast invasion of venous and lymphatic vessels is a frequent event during the first trimester of pregnancy and is compromised in  recurrent spontaneous abortion (RSA). In addition, the present data suggest that EVTs populate regional lymph nodes during pregnancy.WHAT IS ALREADY KNOWNHuman trophoblasts remodel and invade decidual spiral arteries. In addition, a recent report demonstrates that trophoblasts contact and invade decidual veins.STUDY DESIGN, SIZE, DURATIONTissue samples of human first trimester deciduae basalis (n = 54, 6th–13th weeks of gestation) obtained from elective pregnancy terminations were used to study trophoblast invasion into veins and lymphatics, in comparison to arteries. Age-matched cases of idiopathic, recurrent spontaneous abortions tissue samples (n = 23) were assessed for cell numbers of EVTs in these decidual vessels. In addition, lymph nodes of four pregnant women were analysed for the presence of EVTs.PARTICIPANTS/MATERIALS, SETTING, METHODSLocalization, frequency and EVT-mediated targeting and invasion of arterial, venous as well as lymphatic vessels were determined in first trimester decidua basalis tissue sections using immunofluorescence staining with antibodies against CD31, CD34, ephrin B2 (EFNB2), ephrin receptor B4 (EPHB4), HLA-G, podoplanin, prospero-related homeobox 1 (Prox-1), alpha-smooth muscle actin 2 (ATCTA2), von willebrand factor (vWF) and proteoglycan 2 (PRG2). Arterial, venous and lymphatic-associated EVTs were further characterized according to their position in the vascular structure and classified as intramural (im) or intraluminal (il).MAIN RESULTS AND THE ROLE OF CHANCEEVTs, specifically expressing PRG2, target and invade veins and lymphatics in first trimester decidua basalis since HLA-G+ trophoblast were detected in the vascular wall (intramural EVT, imEVTs) and in the lumen of these vessels (intraluminal EVT, ilEVTs). In total, 276 arteries, 793 veins and 113 lymphatics were analysed. While EVTs contact and invade arteries and veins to a similar extent we found that lymphatics are significantly less affected by EVTs (P = 0.001). Moreover, ilEVTs were detected in the lumen of venous and lymphatic vessels, whereas ilEVTs were only found occasionally in the lumen of arteries. Interestingly, RSA tissue sections contained significantly more arterial (P = 0.037), venous (P = 0.002) and lymphatic vessels (P < 0.001), compared to healthy controls. However, while RSA-associated arterial remodeling was unchanged (P = 0.39) the ratios of EVT-affected versus total number of veins (P = 0.039) and lymphatics (P < 0.001) were significantly lower in RSA compared to age-matched healthy decidual sections. Finally, HLA-G+/PRG2+/CD45-EVTs can be detected in regional lymph nodes of pregnant women diagnosed with cervical cancer.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONIn this study, first trimester decidual tissues from elective terminations of pregnancies have been examined and used as a reference for healthy pregnancy. However, this collective may also include pregnancies which would have developed placental disorders later in gestation. Due to limitations in tissue availability our staining results for EVT-specific marker expression in regional lymph nodes of pregnant women are based on four cases only.WIDER IMPLICATIONS OF THE FINDINGSIn this study, we propose migration of HLA-G+ cells into regional lymph nodes during pregnancy suggesting that the human EVT is capable of infiltrating maternal tissues via the blood stream. Moreover, the description of compromised EVT invasion into the venous and lymphatic vasculature in RSA may help to better understand the pathological characteristics of idiopathic recurrent pregnancy loss.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the Austrian Science Fund (grant P-25187-B13 to J.P. and grant P-28417-B30 to M.K.). There are no competing interests to declare.
      PubDate: 2017-03-28
      DOI: 10.1093/humrep/dex058
  • Enhancement of trophoblast differentiation and survival by low molecular
           weight heparin requires heparin-binding EGF-like growth factor
    • Authors: Bolnick AD; Bolnick JM, Kohan-Ghadr H, et al.
      First page: 1218
      Abstract: STUDY QUESTIONDoes low molecular weight heparin (LMWH) require heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) signaling to induce extravillous trophoblast differentiation and decrease apoptosis during oxidative stress?SUMMARY ANSWERLMWH increased HBEGF expression and secretion, and HBEGF signaling was required to stimulate trophoblast extravillous differentiation, increase invasion in vitro and reduce trophoblast apoptosis during oxidative stress.WHAT IS KNOWN ALREADYAbnormal trophoblast differentiation and survival contribute to placental insufficiency syndromes, including preeclampsia and intrauterine growth restriction. Preeclampsia often manifests as a pro-thrombotic state, with unsuccessful transformation of the spiral arteries that reduces oxygen supply and can produce placental infarction. LMWH improves placental function by increasing blood flow. Recent data suggest that the actions of LMWH transcend its anti-coagulative properties, but the molecular mechanism is unknown. There is evidence that LMWH alters the expression of human HBEGF in trophoblast cells, which regulates human trophoblast pathophysiology. HBEGF, itself, is capable of increasing trophoblast survival and invasiveness.STUDY DESIGN, SIZE, DURATIONFirst-trimester placental explants and the HTR-8/SVneo cell line, established using extravillous trophoblast outgrowths from first-trimester villous explants, were treated in vitro with LMWH to examine the effects on HBEGF signaling and trophoblast function under normal physiological and pathological conditions. A highly specific antagonist of HBEGF and other inhibitors of HBEGF downstream signaling were used to determine the relationship between LMWH treatment and HBEGF.PARTICIPANTS/MATERIALS, SETTING, METHODSPlacental tissues (n = 5) were obtained with IRB approval and patient consent from first-trimester terminations. Placental explants and HTR-8/SVneo cells were cultured on plastic or Matrigel™ and treated with a therapeutic dose of LMWH (Enoxaparin; 10 IU/ml), with or without CRM197, pan Erb-B2 Receptor Tyrosine Kinase (ERBB) inhibitor, anti-ERBB1 or ERBB4 blocking antibodies, or pretreatment of cells with heparitinase I. Extravillous differentiation was assessed by immunocytochemistry to determine the relative levels of integrins α6β4 and α1β1. Trophoblast invasiveness was assessed in villous explants by measuring outgrowth from villous tips cultured on Matrigel, and by invasion assays with HTR-8/SVneo cells cultured on Matrigel-coated transwell insert. Placental explants and HTR-8/SVneo cells were exposed to oxidative stress in a hypoxia–reoxygenation (H–R) model, measuring cell death by TUNEL assay, caspase 3 cleavage, and BCL-2α expression.MAIN RESULTS AND THE ROLE OF CHANCELMWH induced extravillous differentiation, according to trophoblast invasion assays and integrin (α6β4–α1β1) switching. Treatment with LMWH rescued cytotrophoblasts and HTR-8/SVneo cells from apoptosis during exposure to reoxygenation injury, based on TUNEL, caspase 3 cleavage and BCL-2α expression. Experiments using CRM197, ERBB1 and ERBB4 blocking antibodies, pan-ERBB inhibitor and removal of cell surface heparin demonstrated that the effects of LMWH on trophoblast invasion and survival were dependent upon HBEGF signaling.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThe primary limitation of this study was the use of only in vitro experiments. Patient demographics from elective terminations were not available.WIDER IMPLICATIONS OF THE FINDINGSThese data provide new insights into the non-coagulation-related aspects of perinatal LMWH treatment in the management of placental insufficiency disorders.STUDY FUNDING/COMPETING INTEREST(S)This research was supported by grants from the National Institutes of Health (HD071408 and HL128628), the March of Dimes, and the W. K. Kellogg Foundation. There were no conflicts or competing interests.
      PubDate: 2017-04-10
      DOI: 10.1093/humrep/dex069
  • Prenatal cerebellar growth trajectories and the impact of periconceptional
           maternal and fetal factors
    • Authors: Koning IV; Dudink JJ, Groenenberg IL, et al.
      First page: 1230
      Abstract: STUDY QUESTIONCAN WE assess human prenatal cerebellar growth from the first until the third trimester of pregnancy and create growth trajectories to investigate associations with periconceptional maternal and fetal characteristics?SUMMARY ANSWERPrenatal growth trajectories of the human cerebellum between 9 and 32 weeks gestational age (GA) were created using three-dimensional ultrasound (3D-US) and show negative associations with pre-pregnancy and early first trimester BMI calculated from self-reported and standardized measured weight and height, respectively.WHAT IS KNOWN ALREADYThe cerebellum is essential for normal neurodevelopment and abnormal cerebellar development has been associated with neurodevelopmental impairments and psychiatric diseases. Cerebellar development is particularly susceptible to exposures during the prenatal period, including maternal folate status, smoking habit and alcohol consumption.STUDY DESIGN, SIZE, DURATIONFrom 2013 until 2015, we included 182 singleton pregnancies during the first trimester as a subgroup in a prospective periconception cohort with follow-up until birth. For the statistical analyses, we selected 166 pregnancies ending in live born infants without congenital malformations.PARTICIPANTS/MATERIALS, SETTING, METHODSWe measured transcerebellar diameter (TCD) at 9, 11, 22, 26 and 32 weeks GA on ultrasound scans. Growth rates were calculated and growth trajectories of the cerebellum were created. Linear mixed models were used to estimate associations between cerebellar growth and maternal age, parity, mode of conception, geographic origin, pre-pregnancy and first trimester BMI, periconceptional smoking, alcohol consumption, timing of folic acid supplement initiation and fetal gender.MAIN RESULTS AND THE ROLE OF CHANCEIn total, 166 pregnancies provided 652 (87%) ultrasound images eligible for TCD measurements. Cerebellar growth rates increased with advancing GA being 0.1691 mm/day in the first trimester, 0.2336 mm/day in the second trimester and 0.2702 mm/day in the third trimester. Pre-pregnancy BMI, calculated from self-reported body weight and height, was significantly associated with decreased cerebellar growth trajectories (β = −0.0331 mm, 95% CI = −0.0638; −0.0024, P = 0.035). A similar association was found between cerebellar growth trajectories and first trimester BMI, calculated from standardized measurements of body weight and height (β = −0.0325, 95% CI = −0.0642; −0.0008, P = 0.045, respectively).LIMITATIONS, REASONS FOR CAUTIONAs the study population largely consisted of tertiary hospital patients, external validity should be studied in the general population. Whether small differences in prenatal cerebellar growth due to a higher pre-pregnancy and first trimester BMI have consequences for neurodevelopmental outcome needs further investigation.WIDER IMPLICATIONS OF THE FINDINGSOur findings further substantiate previous evidence for the detrimental impact of a higher maternal BMI on neurodevelopmental health of offspring in later life.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by the Department of Obstetrics and Gynecology, Erasmus MC University Medical Centre and Sophia Children's Hospital Fund, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared.
      PubDate: 2017-04-27
      DOI: 10.1093/humrep/dex079
  • Elective embryo transfers on Day 6 reduce implantation compared with
           transfers on Day 5
    • Authors: Poulsen VV; Ingerslev HJ, Kirkegaard KK.
      First page: 1238
      Abstract: STUDY QUESTIONIs there a difference in pregnancy rates between embryos transferred electively on Day 5 and Day 6, respectively?SUMMARY ANSWERThe chance of pregnancy is significantly reduced (odds ratio (OR): 0.34; 95% CI 0.22–0.52) if transfer is performed on Day 6 compared with Day 5.WHAT IS KNOWN ALREADYSeveral studies report that Day 5 transfers have higher implantation rates (IRs) when compared with Day 6 transfers. These studies were based on non-elective Day 6 transfers, where transfers on Day 6 were performed with developmentally delayed embryos. Traditionally, difference in IRs has therefore been explained by an impaired embryo quality. An alternative explanation is that endometrial receptivity is higher on Day 5 compared with Day 6.STUDY DESIGN, SIZE, DURATIONThe study was conducted as a retrospective cohort follow-up study on single blastocyst transfers from February 2011 until August 2015 in patients aged <38 years, with ≥eight oocytes retrieved and no diagnosis of endometriosis. Non-elective Day 6 transfers were excluded. Post hoc power-calculations (two-sided level of significance 0.05, power of 0.80) indicate that 91 embryos were needed in each group to detect a reduction in IR (primary outcome) from 40 to 20%.PARTICIPANTS/MATERIALS, SETTING, METHODSDay 5 or Day 6 transfers were implemented accordingly: from 2011 till 2013, transfers were performed on Day 6. If Day 6 was a Sunday, patients received Day 5 transfers. From 2013 onward, blastocysts were transferred on Day 5. If Day 5 was a Sunday, the transfer was delayed to Day 6. Univariable logistic regression analysis was performed to identify potential confounders. Factors with a P-value <0.1 were included in the multivariable logistic regression analysis.MAIN RESULTS AND THE ROLE OF CHANCEWe included 334 single elective Day 5 and 268 elective Day 6 transfers. The unadjusted odds for implantation between Day 5 and Day 6 groups were 0.35 (95% CI 0.25–0.49). A univariable logistic regression analysis identified maternal age, BMI, cumulative FSH dose, number of cryopreserved embryos, score of inner cell mass and trophectoderm and day of transfer as predictors of clinical pregnancy. When adjusting for these variables in a multivariable logistic regression analysis, the implantation odds for Day 5 transfer remained significantly higher than Day 6 (OR 0.34; 95% CI 0.22–0.52).LIMITATIONS, REASONS FOR CAUTIONThe study was conducted on good prognosis patients. The majority of Day 6 transfers were performed in the beginning of the study period. Day 5 transfers were generally performed in the end of the study period. This difference in time of recruitment may cause a minor variation in the data but a subanalysis indicates that this potential variation is negligible. Day 5 scores were higher in the Day 5 transfer group.WIDER IMPLICATIONS OF THE FINDINGSBased on the findings in this study, transfers should be performed on Day 5. If Day 5 transfers are logistically impossible to perform, it is be preferable to cryopreserve the blastocyst and transfer in another cycle on Day 5, as Day 6 transfers should be avoided.STUDY FUNDING/COMPETING INTEREST(S)None.
      PubDate: 2017-04-07
      DOI: 10.1093/humrep/dex059
  • Pregnancy and neonatal outcomes following letrozole use in frozen–thawed
           single embryo transfer cycles
    • Authors: Tatsumi TT; Jwa SC, Kuwahara AA, et al.
      First page: 1244
      Abstract: STUDY QUESTIONAre pregnancy and neonatal outcomes following letrozole use comparable with natural and HRT cycles in patients undergoing single frozen–thawed embryo transfer (FET)?SUMMARY ANSWERLetrozole use was significantly associated with higher rates of clinical pregnancy, clinical pregnancy with fetal heart beat and live birth, and with a lower rate of miscarriage, compared with natural and HRT cycles.WHAT IS KNOWN ALREADYLetrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, the effect of letrozole on pregnancy and neonatal outcomes in FET are not well known.STUDY DESIGN SIZE, DURATIONA retrospective cohort study was conducted using data from the Japanese national ART registry between 2012 and 2013.PARTICIPANTS/MATERIALS SETTING METHODSA total of 110 722 single FET cycles with letrozole (n = 2409), natural (n = 41 470) or HRT cycles (n = 66 843) were included. The main outcomes were the rates of clinical pregnancy, clinical pregnancy with fetal heart beat, miscarriage and live birth. Adjusted odds ratios and relative risks (RRs) were calculated using a generalized estimating equation adjusting for correlations within clinics.MAIN RESULTS AND THE ROLE OF CHANCEThe rates of clinical pregnancy, clinical pregnancy with fetal heart beat, and live birth were significantly higher, while the rate of miscarriage was significantly lower in the letrozole group compared with the natural and HRT groups. In blastocyst stage transfers, the adjusted RRs for clinical pregnancy with fetal heart beat of letrozole compared with natural and HRT cycles were 1.48 (95% CI: 1.41–1.55) and 1.62 (95% CI: 1.54–1.70), respectively. Similarly, the adjusted RRs of letrozole for miscarriage compared with natural and HRT cycles were 0.91 (95% CI: 0.88–0.93) and 0.84 (95% CI: 0.82–0.87), respectively. Neonatal outcomes were mostly similar in letrozole, natural and HRT cycles.LIMITATIONS REASONS FOR CAUTIONImportant limitations of this study included the lack of information concerning the reasons for selecting the specific FET method, parity, the number of previous ART failures, embryo quality and the dose and duration of letrozole intake.WIDER IMPLICATIONS OF THE FINDINGSThese results suggest that letrozole use may improve clinical pregnancy, clinical pregnancy with fetal heart beat, and live births and reduce the risk of miscarriage in patients undergoing single FET cycles.STUDY FUNDING/COMPETING INTEREST(S)No external funding was used for this study. There are no conflicts of interest.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: 2017-04-07
      DOI: 10.1093/humrep/dex066
  • General practitioners’ adherence to work-up and referral
           recommendations in fertility care
    • Authors: van der Pluijm-Schouten HW; Hermens RG, van Heteren CF, et al.
      First page: 1249
      Abstract: STUDY QUESTIONWhat is the current guideline adherence by general practitioners (GPs) for work-up and subsequent referral from primary to secondary care for patients suffering from infertility?SUMMARY ANSWERGuideline adherence by GPs concerning infertility was 9.2% in couples referred.WHAT IS KNOWN ALREADYAdherence to recommendations can decrease unnecessary referral, diagnostics and treatments, and consequently result in lower expenditures. Moreover, patients can be saved from unnecessary hospital visits, emotional burden and out of pocket costs.STUDY DESIGN, SIZE, AND DURATIONA retrospective cohort study among 306 patients referred for basic fertility work-up between January 2011 and June 2013 from primary care to a secondary care teaching hospital or a tertiary hospital with IVF facilities.PARTICIPANTS/MATERIALS, SETTING AND METHODSCouples were eligible to participate when there was no previous referral for fertility problems and the duration of the child wish was <2 years. Data to assess guideline adherence were collected from the referral letter and the medical records. A patient questionnaire was used to determine patients’ general and fertility-related characteristics.MAIN RESULTS AND THE ROLE OF CHANCEThe GP performed a Chlamydia Antibody Titre (CAT) testing and semen analysis as recommended in 15.9% and 42.2% of the referred patients, respectively. According to the guideline, 39% of the couples were under referred (i.e. not immediately referred as recommended), 8.8% were unnecessarily referred and the CAT and semen analysis were unnecessarily repeated in secondary care in 80.0% and 57.1% of cases, respectively.LIMITATIONS REASONS FOR CAUTIONWe could not include non-referred patients with expectant management in primary care, an unknown number of whom became pregnant in this period. This may have resulted in an underestimation of primary care performance.WIDER IMPLICATIONS OF THE FINDINGSOur findings show that guideline adherence concerning work-up and subsequent referral for fertility problems is low. The influence of patient demands for referral remains largely unknown. Barriers and facilitators for guideline adherence should be determined to develop interventions to improve guideline adherence in the areas of work-up and referral for fertility care and to diminish duplicate tests in secondary care.STUDY FUNDING/COMPETING INTEREST(S)Funded by CZ, a Dutch healthcare insurer (grant number AFVV 11-232). CZ had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: None.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: 2017-03-24
      DOI: 10.1093/humrep/dex060
  • Measuring health-related quality of life in women with endometriosis:
           comparing the clinimetric properties of the Endometriosis Health Profile-5
           (EHP-5) and the EuroQol-5D (EQ-5D)
    • Authors: Aubry GG; Panel PP, Thiollier GG, et al.
      First page: 1258
      Abstract: STUDY QUESTIONWhich of the Endometriosis Health Profile-5 (EHP-5) and the EuroQol-5D (EQ-5D) is the most efficient to assess quality of life in women suffering from endometriosis?SUMMARY ANSWERAlthough EHP-5 and EQ-5D instruments had an excellent responsiveness, EHP-5 has a better discriminative ability than EQ-5 to measure health-related quality of life (HrQoL).WHAT IS KNOWN ALREADYProper measurement of HrQoL is important in endometriosis. While many quality of life instruments are available, few have been completely validated in endometriosis. The EHP-5 and the EQ-5D are short and practical scales, which may be useful. Literature is lacking to determine which one is the most suitable in clinical practice or in clinical research.STUDY DESIGN, SIZE, DURATIONThis prospective and observational study conducted between 1 January 2012 and 31 December 2013 included a total of 253 consecutive women with proven endometriosis, undergoing medical or surgical treatment, in 2 French tertiary care centers.PARTICIPANTS/MATERIALS, SETTINGS, METHODSWomen over 18 years consulting for painful symptoms of at least 3 months’ duration or for infertility, with endometriosis proven histologically or radiologically, were requested to fill in the 2 scales before (T0) and 12 months after treatment (T1). Construct validity consisted in testing presupposed relationships between the scales and the characteristics of the patients or the endometriosis. Responsiveness to change was calculated for all patients and in each treatment group. Effect sizes were used according to Cohen's d method.MAIN RESULTS AND THE ROLE OF CHANCEA total of 216 women filled in completely all the questionnaires at T0 and 133 (61.6%) at T1. EHP-5 and EQ-5D had good discriminative abilities regarding the patients’ symptoms, with significant superiority of EHP-5 concerning three of the nine hypotheses. The largest difference was that calculated for the ‘intensity of dysmenorrhea’ using the Visual Analogic Scale, with respectively effect size from Cohen's d (ES) = 0.86 95% CI (0.54–1.17) for EHP-5 versus 0.48 95% CI (0.16–0.79) for EQ-5D. There were no differences in EHP-5 or in EQ-5D scores between subgroups according to the characteristics of endometriosis. Overall responsiveness was excellent and equivalent for EHP-5 and for EQ-5D, with, respectively, ES = 0.81 95% CI (0.56–1.56) versus ES = 0.95 95% CI (0.68–1.20). In subgroup analyses, EHP-5 was responsive in case of medical treatment with ES = 0.93 95% CI (0.07–1.70), whereas EQ-5D was not, ES = 0.73 95% CI (−0.06–1.47).LIMITATIONS, REASONS FOR CAUTIONOur study population included patients with symptomatic and mainly severe forms of endometriosis, which may suggest a spectrum bias. The evaluation of responsiveness in case of medical treatment was based on a small number of patients, which limits the interpretation of the difference found between the two scales in this subgroup.WIDER IMPLICATIONS OF THE FINDINGSEHP-5 is a simple, efficient and valid tool for evaluating quality of life in daily practice and also valuable to provide a primary outcome in clinical studies evaluating treatment efficacy.STUDY FUNDING/COMPETING INTEREST(S)This work was funded by the Direction à la Recherche Clinique et à l'Innovation of Versailles, France. The authors have no conflicts of interest.TRIAL REGISTER NUMBERNone.
      PubDate: 2017-04-04
      DOI: 10.1093/humrep/dex057
  • Grandmaternal smoke exposure reduces female fertility in a murine model,
           with great-grandmaternal smoke exposure unlikely to have an effect
    • Authors: Camlin NJ; Jarnicki AG, Vanders RL, et al.
      First page: 1270
      Abstract: STUDY QUESTIONWhat effect does multigenerational (F2) and transgenerational (F3) cigarette smoke exposure have on female fertility in mice?SUMMARY ANSWERCigarette smoking has a multigenerational effect on female fertility.WHAT IS KNOWN ALREADYIt has been well established that cigarette smoking decreases female fertility. Furthermore, a growing body of evidence suggests that smoking during pregnancy decreases the fertility of daughters and increases cancer and asthma incidence in grandchildren and great-grandchildren.STUDY DESIGN, SIZE, DURATIONSix-week-old C57BL/6 female mice were exposed nasally to cigarette smoke or room air (controls) for 5 weeks prior to being housed with males. Females continued to be exposed to smoke throughout pregnancy and lactation until pups were weaned. A subset of F1 female pups born to these smoke and non-smoke exposed females were bred to create the F2 grandmaternal exposed generation (multigenerational). Finally, a subset of F2 females were bred to create the F3 great-grandmaternal exposed generation (transgenerational). The reproductive health of F2 and F3 females was examined at 8 weeks and 9 months.PARTICIPANTS/MATERIALS, SETTING, METHODSOvarian and oocyte quality was examined in smoke exposed and control animals. A small-scale fertility trial was performed before ovarian changes were examined using ovarian histology and immunofluorescence and/or immunoblotting analysis of markers of apoptosis (TUNEL) and proliferation (proliferating cell nuclear antigen (PCNA) and anti-Mullerian hormone (AMH)). Oocyte quality was examined using immunocytochemistry to analyze the metaphase II spindle and ploidy status. Parthenogenetic activation of oocytes was used to investigate meiosis II timing and preimplantation embryo development. Finally, diestrus hormone serum levels (FSH and LH) were quantified.MAIN RESULTS AND THE ROLE OF CHANCEF2 smoke exposed females had no detectable change in ovarian follicle quality at 8 weeks, although by 9 months ovarian somatic cell proliferation was reduced (P = 0.0197) compared with non-smoke exposed control. Further investigation revealed changes between control and smoke exposed F2 oocyte quality, including altered meiosis II timing at 8 weeks (P = 0.0337) and decreased spindle pole to pole length at 9 months (P = 0.0109). However, no change in preimplantation embryo development was observed following parthenogenetic activation. The most noticeable effect of cigarette smoke exposure was related to the subfertility of F2 females; F2 smoke exposed females displayed significantly increased time to conception (P = 0.0042) and significantly increased lag time between pregnancies (P = 0.0274) compared with non-smoke exposed F2 females. Conversely, F3 smoke exposed females displayed negligible oocyte and follicle changes up to 9 months of age, and normal preimplantation embryo development.LARGE SCALE DATANoneLIMITATIONS, REASONS FOR CAUTIONThis study focused solely on a mouse model of cigarette smoke exposure to simulate human exposure.WIDER IMPLICATIONS OF THE FINDINGSOur results demonstrate that grandmaternal cigarette smoke exposure reduces female fertility in mice, highlighting the clinical need to promote cessation of cigarette smoking in pregnant women.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by the Australian Research Council, National Health and Medical Research Council, Hunter Medical Research Institute, Newcastle Permanent Building Society Charitable Trust, and the University of Newcastle Priory Research Centers in Chemical Biology, Healthy Lungs and Grow Up Well. The authors declare no conflict of interest.
      PubDate: 2017-04-10
      DOI: 10.1093/humrep/dex073
  • Mitochondrial DNA quantification as a tool for embryo viability
           assessment: retrospective analysis of data from single euploid blastocyst
    • Authors: Ravichandran KK; McCaffrey CC, Grifo JJ, et al.
      First page: 1282
      Abstract: STUDY QUESTIONDoes the amount of mitochondrial DNA (mtDNA) in blastocyst biopsy specimens have the potential to serve as a biomarker of euploid embryo implantation ability, independent of morphology?SUMMARY ANSWERThe results of this study strongly suggest that elevated mtDNA levels, above a previously defined threshold, are strongly associated with blastocyst implantation failure and represent an independent biomarker of embryo viability.WHAT IS KNOWN ALREADYImproved methods of embryo selection are highly desirable in order to increase the efficiency of IVF treatment. At present, even the transfer of chromosomally normal embryos of high morphological grade cannot guarantee that a pregnancy will follow. Recently, it has been proposed that the quantity of mtDNA in embryonic cells may be an indicator of developmental potential, with higher levels of mtDNA associated with reduced implantation. However, thus far reported data sets have been relatively small and in some cases have lacked appropriate validation.STUDY DESIGN, SIZE, DURATIONThis large, blinded, retrospective study involved the analysis of relative mtDNA levels in 1505 euploid blastocysts obtained from 490 couples undergoing preimplantation genetic testing for aneuploidy. Implantation outcomes were compared to mtDNA levels in order to determine the capacity of the method to predict viability and to assess the validity of previously established thresholds.PARTICIPANTS/MATERIALS, SETTING, METHODSDNA from blastocyst biopsy samples was amplified and then subjected to aneuploidy analysis using next generation sequencing or array comparative genomic hybridization. Only those embryos classified as chromosomally normal had their mtDNA levels assessed. This analysis was undertaken retrospectively using quantitative real-time PCR, without knowledge of the outcome of embryo transfer. Predictions of implantation failure, based upon mtDNA levels were subsequently compared to the observed clinical results. All cycles involved the transfer of a single embryo.MAIN RESULTS AND THE ROLE OF CHANCEOf all blastocysts analyzed, 9.2% (139/1505) contained mtDNA levels above a previously established viability threshold and were therefore predicted to have reduced chances of implantation. To the date of analysis, 282 euploid blastocysts had been transferred with an overall implantation rate of 65.6% (185/282). Of the transferred embryos, 249 contained levels of mtDNA in the normal range, 185 of which produced a pregnancy, giving an implantation rate of 74.3% for euploid embryos with ‘normal’ quantities of mtDNA. However, 33 of the transferred embryos were determined to have elevated mtDNA quantities. None of these led to a pregnancy. Therefore, the negative predictive value of mtDNA assessment in this cohort was 100% (33/33). The difference between the implantation rates for embryos with normal and elevated mtDNA levels was highly significant (P < 0.0001). The mtDNA thresholds, used for classification of embryos, were unaffected by female age or the clinic in which the IVF was undertaken. The probability of an embryo having elevated levels of mtDNA was not influenced by variation in embryo morphology.LIMITATIONS, REASONS FOR CAUTIONThis study provides strong evidence that mtDNA quantification can serve as a valuable tool to assist the evaluation of blastocyst viability. However, to determine the true extent of any clinical benefits, other types of investigations, such as non-selection studies and randomized controlled trials, will also be necessary.WIDER IMPLICATIONS OF THE FINDINGSThe results of this study suggest that mtDNA quantity can serve as an independent biomarker for the prediction of euploid blastocyst implantation potential. Prospective studies should now be undertaken to confirm these results. Additionally, investigations into the underlying biological cause(s) of elevated mtDNA levels and an enhanced understanding of how they relate to diminished implantation potential would be invaluable.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by funding provided by Reprogenetics. None of the authors have any competing interests.
      PubDate: 2017-04-06
      DOI: 10.1093/humrep/dex070
  • Tri-directional anaphases as a novel chromosome segregation defect in
           human oocytes
    • Authors: Haverfield J; Dean NL, Nöel D, et al.
      First page: 1293
      Abstract: STUDY QUESTIONWhat are the chromosome segregation errors in human oocyte meiosis-I that may underlie oocyte aneuploidy?SUMMARY ANSWERMultiple modes of chromosome segregation error were observed, including tri-directional anaphases, which we attribute to loss of bipolar spindle structure at anaphase-I.WHAT IS KNOWN ALREADYOocyte aneuploidy is common and associated with infertility, but mechanistic information on the chromosome segregation errors underlying these defects is scarce. Lagging chromosomes were recently reported as a possible mechanism by which segregation errors occur.STUDY DESIGN, SIZE, DURATIONLong-term confocal imaging of chromosome dynamics in 50 human oocytes collected between January 2015 and May 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSGerminal vesicle (GV) stage oocytes were collected from women undergoing intracytoplasmic sperm injection cycles and also CD1 mice. Oocytes were microinjected with complementary RNAs to label chromosomes, and in a subset of oocytes, the meiotic spindle. Oocytes were imaged live through meiosis-I using confocal microscopy. 3D image reconstruction was used to classify chromosome segregation phenotypes at anaphase-I. Segregation phenotypes were related to spindle dynamics and cell cycle timings.MAIN RESULTS AND THE ROLE OF CHANCEMost (87%) mouse oocytes segregated chromosomes with no obvious defects. We found that 20% of human oocytes segregated chromosomes bi-directionally with no lagging chromosomes. The rest were categorised as bi-directional anaphase with lagging chromosomes (20%), bi-directional anaphase with chromatin mass separation (34%) or tri-directional anaphase (26%). Segregation errors correlated with chromosome misalignment prior to anaphase. Spindles were tripolar when tri-directional anaphases occurred. Anaphase phenotypes did not correlate with meiosis-I duration (P = 0.73).LARGE SCALE DATANot applicable.LIMITATIONS, REASONS FOR CAUTIONOocytes were recovered at GV stage after gonadotrophin-stimulation, and the usual oocyte quality caveats apply. Whilst the possibility that imaging may affect oocyte physiology cannot be formally excluded, detailed controls and justifications are presented.WIDER IMPLICATIONS OF THE FINDINGSThis is one of the first reports of live imaging of chromosome dynamics in human oocytes, introducing tri-directional anaphases as a novel potential mechanism for oocyte aneuploidy.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by grants from Fondation Jean-Louis Lévesque (Canada), CIHR (MOP142334) and CFI (32711) to GF. JH is supported by Postdoctoral Fellowships from The Lalor Foundation and CIHR (146703). The authors have no conflict of interest.
      PubDate: 2017-04-25
      DOI: 10.1093/humrep/dex083
  • Synergistic effect of regulatory T cells and proinflammatory cytokines in
           angiogenesis in the endometriotic milieu
    • Authors: Wang X; Zhou W, Luo X, et al.
      First page: 1304
      Abstract: STUDY QUESTIONDo regulatory T cells (Tregs) contribute to angiogenesis in endometriosis?SUMMARY ANSWERHigh levels of CCL17 and CCL22 cause the recruitment of Tregs, upregulate the immunosuppression of Tregs and, in turn, may promote angiogenesis in endometrial cells in synergy with proinflammatory cytokines.WHAT IS ALREADY KNOWNThe peritoneal fluid of patients with endometriosis has a higher percentage of Tregs than that of normal individuals; however, the regulatory role of Tregs in the disease remains unclear.STUDY DESIGN, SIZE, DURATIONThis study used primary human endometrial stromal cells (ESCs), monocytes (Mo), Tregs and human umbilical vein endothelial cells (HUVECs). All experiments were performed at least three times.PARTICIPANTS/MATERIALS, SETTING, METHODSThe migration of Tregs was evaluated by the transwell migration assay. The activation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase and p38 signaling pathways was examined using the In-Cell WesternTM (LI-COR®) western blot analysis system, as well as by traditional western blot analysis. Changes in the expression of CCL22, CCL17, transforming growth factor-beta 1 (TGF-β1), Interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), IL-8 and vascular endothelial growth factor (VEGF) in cell-culture supernatant were detected by ELISA. We analyzed the Tregs by multicolor flow cytometry to directly test the expression of CCR4, CD4, CD25, Foxp3, CTLA-4, CD39 and CD73.MAIN RESULTS AND THE ROLE OF CHANCEOur results showed that ESCs-Mo co-culture produced significantly higher levels of CCL22 and CCL17 than ESCs or Mo cultured alone, and that estradiol (E2) or progesterone (P) further promoted this upregulation, demonstrating stronger chemotaxis on Tregs. The co-culture of ESCs with Mo stimulated TGF-β1 secretion by Tregs, which could be inhibited by anti-CCL22 or/and anti-CCL17 neutralizing antibodies (Abs). The expression of CCR4 by Tregs was upregulated in ESCs-Mo co-culture, especially by treatment with E2 and/or P, and this effect could be abolished by anti-CCL22 and/or anti-CCL17-neutralizing Abs. The Treg-ESCs-Mo co-culture treated with E2 (10−8 mol/l) and P (10−8 mol/l) could enhance the immunosuppression of Tregs, as proved by the elevated expression of Foxp3, CTLA-4, CD39 and CD73 on Tregs. ESCs-Mo co-culture could significantly promote the secretion of IL-1β and TNF-α. TGF-β1 from Tregs could activate p38/ERK1/2 signaling pathways in ESCs, and IL-1β and TNF-α produced by ESCs-Mo co-culture had synergistic roles with TGF-β1. TGF-β1 and the proinflammatory cytokines IL-1β or TNF-α could synergistically promote IL-8 and VEGF expression in ESCs via the p38/ERK1/2 signaling pathways. The high levels of IL-8 and VEGF in the supernatant of ESCs stimulated the angiogenesis of HUVECs.LARGE SCALE DATANone.LIMITATIONS, REASONS FOR CAUTIONThis study was only performed in vitro using eutopic ESCs, instead of ectopic cells, from endometriosis patients. Therefore, it is necessary to do further experiments to determine whether Tregs promote angiogenesis in the endometriotic milieu in synergy with proinflammatory cytokines in vivo.WIDER IMPLICATIONS OF THE FINDINGSCo-targeting Tregs and proinflammatory cytokines may be an effective treatment for endometriosis.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by Ministry of Science and Technology of China 2015CB943300 to L.D.-J.; National Natural Science Foundation of China, item number 81200425 to  W.X.-Q.; National Natural Science Foundation of China, item number 81471548 to L.D.-J.; and The Research Fund for the Doctoral Program of Higher Education of China to W.X.-Q. (20110071120093). The authors have no conflicts of interest to declare.
      PubDate: 2017-04-04
      DOI: 10.1093/humrep/dex067
  • Angiotensin-(1–7) in human follicular fluid correlates with oocyte
    • Authors: Cavallo IK; Dela Cruz C, Oliveira ML, et al.
      First page: 1318
      Abstract: STUDY QUESTIONDo angiotensin (Ang)-(1–7) levels in human ovarian follicular fluid (FF) correlate with the number and proportion of mature oocytes obtained for IVF?SUMMARY ANSWERThe present study shows for the first time that Ang-(1–7) levels in human FF correlate with the proportion of mature oocytes collected upon ovarian stimulation for IVF.WHAT IS KNOWN ALREADYAng-(1–7) is an active peptide of the renin-angiotensin system that stimulates oocyte maturation in isolated rabbit and rat ovaries. However, its role in human ovulation remains unexplored.STUDY DESIGN, SIZE, DURATIONThis was a prospective cohort study including 64 participants from a single IVF center. Sample size was calculated to achieve a statistical power of 80% in detecting 20% differences in the proportion of mature oocytes between groups. The participants were enrolled in the study during six consecutive months.PARTICIPANTS/MATERIALS, SETTING, METHODSPlasma samples were obtained from all subjects at Day 21 of the last menstrual cycle before starting pituitary blockade and controlled ovarian stimulation (COS). Plasma and FF samples were quickly mixed with a protease inhibitor cocktail and stored at −80°C. Ang-(1–7) was quantified in plasma and FF samples by a highly sensitive and specific radioimmunoassay, which was preceded by solid phase extraction, speed vacuum concentration and sample reconstitution in assay buffer. FF Ang-(1–7) levels were stratified into tertiles and the patients of each tertile were compared for COS/IVF outcomes using Kruskal–Wallis ANOVA. Multiple regression analysis was used to adjust correlations for potential confounders. The mRNA encoding for Mas, a receptor for Ang-(1–7), was investigated by real-time PCR in luteinized granulosa cells purified from the FF.MAIN RESULTS AND THE ROLE OF CHANCEThere was a four-fold increase in plasma Ang-(1–7) after ovulation induction (median 160.9 vs 41.4 pg/ml, P < 0.0001). FF Ang-(1–7) levels were similar to (169.9 pg/ml) but did not correlate with plasma Ang-(1–7) levels (r = −0.05, P = 0.665). Patients at the highest FF Ang-(1–7) tertile had a higher proportion of mature oocytes compared to patients at the lower FF Ang-(1–7) tertile (median 100% vs 70%, P < 0.01). There was a linear correlation between FF Ang-(1–7) and the proportion of mature oocytes (r = 0.380, P < 0.01), which remained significant after adjustment for age and duration of infertility (r = 0.447, P < 0.001). The luteinized granulosa cells expressed Mas receptor mRNA, which was positively correlated to the number of mature oocytes in women with more than three mature oocytes retrieved (r = 0.42, P < 0.01).LIMITATIONS, REASONS FOR CAUTIONThis is an observational study, therefore, no causal relationship can be established between Ang-(1–7) and human oocyte maturation. Mas protein expression was not quantified due to limited availability of granulosa cells.WIDER IMPLICATIONS OF THE FINDINGSSince this peptide promotes oocyte maturation in other species, it deserves further investigation as a potential maturation factor to human oocytes.STUDY FUNDING AND COMPETING INTEREST(S)Research supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG). The authors have nothing to disclose.
      PubDate: 2017-04-10
      DOI: 10.1093/humrep/dex072
  • Transitions in pregnancy planning in women recruited for a large
           prospective cohort study
    • Authors: Luderer UU; Li TT, Fine JP, et al.
      First page: 1325
      Abstract: STUDY QUESTIONDo the rates at which women transition among different intensities of pregnancy planning vary with age, marital status and race/ethnicity?SUMMARY ANSWERRates of transition from low or moderate pregnancy probability groups (PPGs) to higher PPGs vary by age, marital status and race/ethnicity.WHAT IS KNOWN ALREADYThe design of prospective studies of the effects of pre- and peri-conception exposures on fecundity, pregnancy and children's health is challenging because at any specific time only a small percentage of reproductive age women is attempting to conceive. To our knowledge, there has been no population-based, prospective study that repeatedly assessed pregnancy planning, which included women who were not already planning pregnancy at enrollment and whose ages spanned the female reproductive age range.STUDY DESIGN, SIZE, DURATIONA longitudinal study was carried out that repeatedly assessed pregnancy probability in 12 916 women for up to 21 months from January 2009 to September 2010.PARTICIPANTS/MATERIALS, SETTING, METHODWe analyzed data from the National Children's Study Vanguard Study, a pilot study for a large-scale epidemiological birth cohort study of children and their parents. During the Vanguard Study, investigators followed population-based samples of reproductive age women in each of seven geographically dispersed and diverse study locations over time to identify when they sought to become pregnant, providing a unique opportunity to prospectively assess changes in pregnancy planning in a large sample of US women. At study entry and each follow-up contact, which occurred at 1, 3 or 6 month intervals depending on PPG, a questionnaire was used to assess behavior dimensions of pregnancy planning to assign women to low, moderate, high non-tryer and high tryer PPGs.MAIN RESULTS AND THE ROLE OF CHANCECrude rates of pregnancy increased with higher assigned PPG, validating the utility of the instrument. The initial PPG and probabilities of transitioning from low or moderate PPG to higher PPG or pregnancy varied with age, marital status and race/ethnicity. Women aged 25 to <35 years had shorter times to transition to higher PPGs or to pregnant compared with women <25 years. Women who were not currently married had longer times to transition from any initial PPG to pregnant, high tryer or high non-tryer status than currently married women. Non-Hispanic Black (NHB) and Hispanic women had shorter time to transition from low or moderate to high non-tryer than non-Hispanic White (NHW) women. NHB women also had shorter time to transition from low to high tryer than NHW women. High tryers are more likely to be aged 25 to <30 years, to be married, and to be Hispanic, NHB or other race/ethnicity than women in the low PPG.LIMITATIONS, REASONS FOR CAUTIONLoss to follow-up varied by age, marital status and race/ethnicity. Although weights were not developed for the Vanguard study, the self-weighting design minimizes the bias of unweighted analysis. Nonetheless, the SEs for some estimates may be under-estimated.WIDER IMPLICATIONS OF THE FINDINGSOur results show that demographic characteristics are strong predictors of women's behaviors toward pregnancy. The results further show that frequent follow-up assessments of pregnancy planning behavior in large numbers of women are required to recruit an unbiased sample of preconception women. These findings will be useful to investigators designing prospective studies of fecundability, pregnancy outcomes and children's health.STUDY FUNDING/COMPETING INTERESTSNational Institutes of Health (contracts N01-HD53414, N01-HD63416, N01-HD53410, N01-HD53415, N01-HD53396, N01-HD53413 and N01-HD-53411; grant R21 ES016846) and by the University of California Irvine Center for Occupational and Environmental Health. No competing interests.TRIAL REGISTRATION NUMBERNone.
      PubDate: 2017-04-07
      DOI: 10.1093/humrep/dex065
  • Semen quality of young men from the general population in Baltic countries
    • Authors: Erenpreiss J; Punab M, Zilaitiene B, et al.
      First page: 1334
      Abstract: STUDY QUESTIONWhat are the parameters of semen quality in Baltic men?SUMMARY ANSWERCombined parameters of sperm concentration, motility and morphology revealed that 11–15% of men had low semen quality, 37–50% intermediate and 38–52% high semen quality.WHAT IS KNOWN ALREADYPrevious studies have revealed regional differences in semen parameters, and semen quality of Baltic men has been suggested to be better than that of other European men.STUDY DESIGN, SIZE, DURATIONThis was a cross-sectional study of 1165 men aged 16–29 years from Estonia (N = 573), Latvia (N = 278) and Lithuania (N = 314) conducted in 2003–2004.PARTICIPANTS/MATERIALS SETTING METHODSMen from the general population, median age 19.8 years, provided one semen sample each, had blood samples taken, had testis size determined, and provided information on lifestyle. Based on combined data of sperm concentration, sperm motility and morphology the cohort was classified into three categories: low, intermediate or high semen quality. Comparisons between groups (including subgroups of Estonian men of Russian versus Estonian ethnicity) were tested, adjusting for ejaculation abstinence and age.MAIN RESULTS AND THE ROLE OF CHANCEThe median sperm concentration of the Estonian, Latvian and Lithuanian populations of Baltic men was 63 mill/ml. Low semen quality was detected in 11–15% of the men, intermediate in 37–50% and high in 38–52%. No crucial differences between national subgroups were detected, except that a higher percentage (9.6%) of the subgroup of Russian Estonians reported having had cryptorchidism compared to the other men (2.5–3.6%, P < 0.001). Smoking had an adverse impact on both sperm concentration and total sperm counts (P < 0.001).LIMITATIONS REASONS FOR CAUTIONThe semen quality data were collected >10 years ago. Thus, a recent change in semen quality cannot be excluded. Owing to the study design, it is assumed, but unproven, that the men were representative of the general populations. Some men were very young (16 years), however, this was also the case for other European studies of similar populations. Assessment of sperm motility is associated with inter-observer variation, and no quality control was undertaken for sperm motility assessment to account for that. Thus, estimates of sperm motility should be interpreted with caution.WIDER IMPLICATIONS OF THE FINDINGSAnalysis of the semen variables separately did not identify that a considerable percentage of Baltic men had low semen quality. The combined analysis, however, showed that more than one out of nine men had semen quality at a level indicating reduced fertility chances. We suggest that future studies of semen quality should be carried out reporting both results of single semen parameters and estimates that combine the most frequently assessed variables.STUDY FUNDING/COMPETING INTEREST(S)The study was funded by the EU fifth framework project Number QLK4-1999-01422 ‘Envir.Repro.Health’ extension to Baltic countries Number QLRT-2001–02911; Estonian Science Foundation, grant numbers 2991 and PUT181. There are no competing interests.TRIAL REGISTRATION NUMBERN/A.
      PubDate: 2017-04-05
      DOI: 10.1093/humrep/dex062
  • Two-year development of children conceived by IVM: a prospective
           controlled single-blinded study
    • Authors: Roesner SS; von Wolff MM, Elsaesser MM, et al.
      First page: 1341
      Abstract: STUDY QUESTIONIs there a difference in mental development of children conceived by IVM in comparison to IVF or ICSI, independently, at the age of 2 years?SUMMARY ANSWERNo differences could be found in mental development of IVM children compared to IVF and IVM children compared to ICSI as well.WHAT IS KNOWN ALREADYOnly few retrospective or non-controlled studies addressed the health of IVM children and did not show a negative impact of the IVM procedure.STUDY DESIGN, SIZE, DURATIONProspective controlled single-blinded study including 63 pregnancies (21 per IVM, IVF and ICSI groups) with 70 children expected. Examinations of 62 embryos at first trimester screening, of 57 fetuses at 21st week of pregnancy, of 60 children at birth and of 37 children at their second birthday were performed during the study period from January 2009 until October 2016. Bayley score at the age of 2 was the primary outcome parameter. Data of 40 children after spontaneous conception from a previous prospective unrelated study were further used as control at 2 years examination and compared to the pooled ART group (IVM, IVF and ICSI).PARTICIPANTS/MATERIALS, SETTING, METHODSTwenty-one IVM pregnancies achieved in the study period were included. For each of them, the following IVF- and ICSI pregnancies were recruited as controls. Ultrasound examinations during pregnancy, examinations of newborns and of children around their second birthday were done by blinded prenatal specialists, pediatricians and neuropediatricians, respectively.MAIN RESULTS AND THE ROLE OF CHANCEChildren conceived after IVM did not show differences during embryonic development, at birth nor in their neuropediatric development at the age of 2 compared to their counterparts after IVF and after ICSI (Bayley score 91.3 ± 21.0 for IVM, 96.8 ± 13.2 for IVF and 103.9 ± 13.1 for ICSI) and of the pooled ART group compared to children after spontaneous conception (96.6 ± 16.4 ART and 103.2 ± 9.4 spontaneous conception). When analyzing singleton pregnancies only, again no differences during pregnancy, at birth and at their 2-year evaluation were detected between IVM versus IVF and IVM versus ICSI.LIMITATIONS, REASONS FOR CAUTIONDue to the small sample size data must be interpreted with caution. To allow a confirmative answer that there are no health risks for children conceived by IVM, large multicenter cohort or registry-based studies are urgently needed.WIDER IMPLICATIONS OF THE FINDINGSThe study adds further information to previous uncontrolled or retrospective studies, which were unable to detect risks for the health of IVM children.STUDY FUNDING/COMPETING INTEREST(S)The study was supported by the ‘Deutsche Forschungsgemeinschaft’ (DFG): STR 387/4-1. G.R. receives royalties from Pearson Assessment Germany (editor fee for Bayley-III). The other authors have no conflicts of interest to declare.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: 2017-04-06
      DOI: 10.1093/humrep/dex068
  • Risks of miscarriage or preterm delivery in trichorionic and dichorionic
           triplet pregnancies with embryo reduction versus expectant management: a
           systematic review and meta-analysis
    • Authors: Anthoulakis CC; Dagklis TT, Mamopoulos AA, et al.
      First page: 1351
      Abstract: STUDY QUESTIONIs pregnancy outcome in triplet pregnancies improved with embryo reduction (ER) to twins compared to expectant management?SUMMARY ANSWERIn trichorionic triplet pregnancies, ER to twins reduces the risk of preterm birth (<34 weeks) without significantly increasing the risk of miscarriage (<24 weeks), whereas in dichorionic triplet pregnancies, the results are inconclusive.WHAT IS KNOWN ALREADYTriplet pregnancies are associated with a high risk of miscarriage and preterm birth. ER can ameliorate these conditions in higher order multiple gestations but is still controversial in triplets.STUDY DESIGN, SIZE, DURATIONThis study aimed to conduct a systematic review, following the PRISMA guidelines, and critically appraise ER at 8–14 weeks of gestation in both trichorionic triamniotic (TCTA) and dichorionic triamniotic (DCTA) pregnancies. Selective ER to twins was compared with expectant management, focusing on the risks of miscarriage and preterm birth. The computerized database search was performed on 8 January 2017. Overall, from 25 citations of relevance, eight studies with a total of 249 DCTA and 1167 TCTA pregnancies fulfilled the inclusion criteria.PARTICIPANTS/MATERIALS, SETTING, METHODSA comprehensive computerized systematic literature search of all English language studies between 2000 and 2016 was performed in PubMed, EMBASE, Scopus, Evidence Based Medicine Reviews (Cochrane Database and Cochrane Central Register of Controlled Trials) and Google Scholar. Relevant article reference lists were hand searched. The management options were compared for rates of miscarriage <24 weeks and preterm birth <34 weeks. Only studies with both expectant management and ER to twins were included in the analysis. The quality of each individual article was critically appraised and appropriate statistical methods were used to extract results.MAIN RESULTS AND THE ROLE OF CHANCEIn TCTA pregnancies managed expectantly (n = 501), the rates of miscarriage and preterm birth were 7.4 and 50.2%, respectively. Meta-analysis demonstrated that ER to twins in TCTA pregnancies (n = 666) was associated with a lower risk (17.3 versus 50.2%) of preterm birth (RR = 0.36, 95% CI: 0.28–0.48), whereas the risk of miscarriage (8.1% versus 7.4%) did not significantly increase (RR = 1.08, 95% CI: 0.58–1.98). In DCTA triplets managed expectantly (n = 200), the rates of miscarriage and preterm birth were 8.5 and 51.9%, respectively. Although the meta-analysis was inconclusive, it suggested that ER to twins in DCTA triplets, either of the foetus with a separate placenta (n = 15) or one of the monochorionic pair (n = 34), was neither significantly associated with an increased risk of miscarriage (8.5 versus 13.3%, P = 0.628 and RR = 1.22, 95% CI: 0.38–3.95, respectively) nor with a lower risk of preterm birth (51.9 versus 46.2%, P = 0.778 and RR = 0.5, 95% CI: 0.04–5.7, respectively).LIMITATIONS, REASONS FOR CAUTIONNo randomized controlled trials of ER versus expectant management in TCTA or DCTA pregnancies were identified from our literature search. We were able to include only a handful of papers with small sample sizes and suffering from bias, and non-English publications were missed. Irrespective of the strict inclusion and exclusion criteria, publication bias was evident.WIDER IMPLICATIONS OF THE FINDINGSThe greatest strength of our systematic review is that, contrary to the existing literature, it only included studies with both the intervention and expectant arm. Our results are in agreement with current literature. In TCTA pregnancies, ER to twins is associated with a lower risk of preterm birth but is not associated with a higher risk of miscarriage. In the absence of a randomized trial, the data from systematic reviews appear to be the best existing evidence for counselling in the first trimester on the different options available. Finally, in DCTA pregnancies, indications exist that ER (of one of the MC pair) to twins could possibly reduce the risk of preterm birth without increasing the risk of miscarriage.STUDY FUNDING/COMPETING INTEREST(S)None to declare.REGISTRATION NUMBERN/A.
      PubDate: 2017-04-21
      DOI: 10.1093/humrep/dex084
  • Cord blood androgen measurements: the importance of assay validation
    • Authors: Keelan. J; Hickey M, Hollier LP.
      First page: 1360
      PubDate: 2017-04-27
      DOI: 10.1093/humrep/dex075
  • Reply I. Cord blood androgen measurement: the importance of assay
    • Authors: Huo X; Liu C.
      First page: 1361
      PubDate: 2017-04-27
      DOI: 10.1093/humrep/dex077
  • Reply II. Cord blood androgen measurements: the importance of assay
    • Authors: Warembourg C; Garlantézec R, Cordier S.
      First page: 1363
      PubDate: 2017-04-27
      DOI: 10.1093/humrep/dex076
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