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Publisher: Oxford University Press   (Total: 406 journals)

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Showing 1 - 200 of 406 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (SJR: 0.189, CiteScore: 0)
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.79, CiteScore: 2)
Adaptation     Hybrid Journal   (Followers: 9, SJR: 0.143, CiteScore: 0)
Advances in Nutrition     Hybrid Journal   (Followers: 53, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.434, CiteScore: 1)
Aesthetic Surgery J. Open Forum     Open Access  
African Affairs     Hybrid Journal   (Followers: 66, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 90, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 19, SJR: 1.376, CiteScore: 3)
American Entomologist     Full-text available via subscription   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 169, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 178, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 197, SJR: 2.713, CiteScore: 3)
American J. of Health-System Pharmacy     Full-text available via subscription   (Followers: 52, SJR: 0.595, CiteScore: 1)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.322, CiteScore: 3)
American J. of Jurisprudence     Hybrid Journal   (Followers: 19, SJR: 0.281, CiteScore: 1)
American J. of Legal History     Full-text available via subscription   (Followers: 9, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 16, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 22, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal   (Followers: 1)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 16, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 38, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 56, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 10, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 34, SJR: 0.728, CiteScore: 2)
Antibody Therapeutics     Open Access  
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 17, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 59, SJR: 2.987, CiteScore: 3)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 1.241, CiteScore: 1)
Arbitration Intl.     Full-text available via subscription   (Followers: 21)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 44, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 52, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 338, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 29, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 17, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 185, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 65)
Brain     Hybrid Journal   (Followers: 68, SJR: 5.858, CiteScore: 7)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 50, SJR: 2.505, CiteScore: 5)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 2.15, CiteScore: 3)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 36, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 604, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 86, SJR: 1.019, CiteScore: 2)
British Medical Bulletin     Hybrid Journal   (Followers: 6, SJR: 1.355, CiteScore: 3)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 34)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 70, SJR: 0.764, CiteScore: 2)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 12, SJR: 2.438, CiteScore: 4)
Cambridge Quarterly     Hybrid Journal   (Followers: 10, SJR: 0.104, CiteScore: 0)
Capital Markets Law J.     Hybrid Journal   (Followers: 2, SJR: 0.222, CiteScore: 0)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.135, CiteScore: 5)
Cardiovascular Research     Hybrid Journal   (Followers: 14, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 48, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 22, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.246, CiteScore: 0)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 5, SJR: 0.412, CiteScore: 0)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 10, SJR: 1.392, CiteScore: 2)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.183, CiteScore: 0)
Classical Receptions J.     Hybrid Journal   (Followers: 27, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 1)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 69, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 24, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 27, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.268, CiteScore: 1)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.319, CiteScore: 1)
Conservation Physiology     Open Access   (Followers: 3, SJR: 1.818, CiteScore: 3)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 2)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 3, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 9, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 14, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 21, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 5, SJR: 2.866, CiteScore: 6)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 4)
Early Music     Hybrid Journal   (Followers: 17, SJR: 0.139, CiteScore: 0)
Econometrics J.     Hybrid Journal   (Followers: 32, SJR: 2.926, CiteScore: 1)
Economic J.     Hybrid Journal   (Followers: 113, SJR: 5.161, CiteScore: 3)
Economic Policy     Hybrid Journal   (Followers: 46, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 24, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 56, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 17, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.818, CiteScore: 2)
Environmental Epigenetics     Open Access   (Followers: 2)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.408, CiteScore: 1)
EP-Europace     Hybrid Journal   (Followers: 3, SJR: 2.748, CiteScore: 4)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 4.505, CiteScore: 8)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 19, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 66, SJR: 9.315, CiteScore: 9)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 10, SJR: 3.625, CiteScore: 3)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 2)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. : Case Reports     Open Access  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.223, CiteScore: 0)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.681, CiteScore: 2)
European J. of Intl. Law     Hybrid Journal   (Followers: 200, SJR: 0.694, CiteScore: 1)
European J. of Orthodontics     Hybrid Journal   (Followers: 5, SJR: 1.279, CiteScore: 2)
European J. of Public Health     Hybrid Journal   (Followers: 20, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 10, SJR: 1.172, CiteScore: 2)
European Review of Economic History     Hybrid Journal   (Followers: 30, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 43, SJR: 2.728, CiteScore: 3)
Evolution, Medicine, and Public Health     Open Access   (Followers: 12)
Family Practice     Hybrid Journal   (Followers: 16, SJR: 1.018, CiteScore: 2)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 16, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 28, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 32, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.308, CiteScore: 3)
Food Quality and Safety     Open Access   (Followers: 1)
Foreign Policy Analysis     Hybrid Journal   (Followers: 24, SJR: 1.425, CiteScore: 1)
Forest Science     Hybrid Journal   (Followers: 8, SJR: 0.89, CiteScore: 2)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 1.133, CiteScore: 3)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.104, CiteScore: 0)
French History     Hybrid Journal   (Followers: 33, SJR: 0.118, CiteScore: 0)
French Studies     Hybrid Journal   (Followers: 21, SJR: 0.148, CiteScore: 0)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.152, CiteScore: 0)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 16, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 39, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 23, SJR: 0.161, CiteScore: 0)
GigaScience     Open Access   (Followers: 5, SJR: 5.022, CiteScore: 7)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 13, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 57, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 16, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 24, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 22, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 33, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 28, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 15, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 72, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 20, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 62, SJR: 0.756, CiteScore: 1)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 58, SJR: 1.591, CiteScore: 3)
ICSID Review : Foreign Investment Law J.     Hybrid Journal   (Followers: 10)
ILAR J.     Hybrid Journal   (Followers: 2, SJR: 1.732, CiteScore: 4)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.679, CiteScore: 1)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.538, CiteScore: 1)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.496, CiteScore: 1)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 1.987, CiteScore: 2)
Industrial and Corporate Change     Hybrid Journal   (Followers: 9, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 39, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 47, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Innovation in Aging     Open Access  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 9, SJR: 1.319, CiteScore: 2)
Integrative Biology     Full-text available via subscription   (Followers: 6, SJR: 1.36, CiteScore: 3)
Integrative Organismal Biology     Open Access  
Interacting with Computers     Hybrid Journal   (Followers: 11, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 66, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 26)
Intl. Health     Hybrid Journal   (Followers: 6, SJR: 0.851, CiteScore: 2)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 36, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 64, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 245, SJR: 3.969, CiteScore: 5)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.202, CiteScore: 1)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 28, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, SJR: 0.285, CiteScore: 1)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.403, CiteScore: 1)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.808, CiteScore: 4)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 11, SJR: 1.545, CiteScore: 1)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 38, SJR: 0.389, CiteScore: 1)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 11, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 40, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 23, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 49, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 25, SJR: 1.201, CiteScore: 1)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 2, SJR: 0.15, CiteScore: 0)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.103, CiteScore: 0)
J. of African Economies     Hybrid Journal   (Followers: 17, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 46, SJR: 0.297, CiteScore: 1)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, SJR: 1.065, CiteScore: 2)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 15, SJR: 2.419, CiteScore: 4)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 5, SJR: 0.585, CiteScore: 1)
J. of Biochemistry     Hybrid Journal   (Followers: 41, SJR: 1.226, CiteScore: 2)
J. of Breast Imaging     Full-text available via subscription  
J. of Burn Care & Research     Hybrid Journal   (Followers: 10, SJR: 0.768, CiteScore: 2)

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Similar Journals
Journal Cover
Human Reproduction
Journal Prestige (SJR): 2.643
Citation Impact (citeScore): 5
Number of Followers: 72  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0268-1161 - ISSN (Online) 1460-2350
Published by Oxford University Press Homepage  [406 journals]
  • Is it time to reconsider how to manage oocytes affected by smooth
           endoplasmic reticulum aggregates'
    • Authors: Ferreux L; Sallem A, Chargui A, et al.
      Pages: 591 - 600
      Abstract: STUDY QUESTIONDid the revised Alpha/ESHRE consensus (Vienna, 2017) bring a real answer on managing oocytes with aggregates of smooth endoplasmic reticulum (SERa)'SUMMARY ANSWERAccording to the currently available literature, a case by case approach on the time of injecting/inseminating SERa+ oocytes may be not helpful for embryologists making a decision, so we suggest fertilizing both SERa+ and SERa− oocytes and prioritizing embryos derived from SERa− oocytes.WHAT IS KNOWN ALREADY'In 2011, the Istanbul consensus recommended not to inject/inseminate SER+ oocytes due to adverse foetal outcomes reported in literature. At the end of 2017, a panel of experts reconsidered this recommendation and advised a case by case approach. Hence, with a lack of clear recommendations, in-vitro fertilization practitioners still have heterogeneous attitudes when managing SERa+ oocytes. In this context of controversy, an updated review could be helpful in (i) forming a common language for managing cases of SERa+ oocytes and (ii) offering the most ethical practice and best care for patients seeking infertility treatment or fertility preservation.STUDY DESIGN, SIZE, DURATIONThis review (with a last literature search on 1 June 2018) evaluated the effect of the SER dysmorphism on embryological and neonatal outcomes.PARTICIPANTS/MATERIALS, SETTING, METHODSStudies were considered for inclusion if they were prospective or retrospective cohort or case–control studies. Electronic searches of the Pubmed and Embase databases were done using the keyword combination: smooth endoplasmic reticulum, SER, oocyte and zygote. s and articles written in English and limited to humans were included.MAIN RESULTS AND THE ROLE OF CHANCEThe search returned a total of 726 studies among which 21 met the inclusion criteria. The literature does not unanimously support a negative association between SERa and embryogenesis, implantation or assisted reproductive therapy outcomes. The reviewed studies reported 112 neonatal outcomes after transfers where at least one embryo originated from oocyte affected by SERa. They included 101 healthy babies, three live births with malformations, three neonatal deaths, one stillbirth and four medical interruptions of pregnancy. After transfer of embryos exclusively derived from SERa+ oocytes, a total of 48 healthy newborns were reported along with four babies with perinatal complications (including one ventricular septal defect), one stillbirth, one neonatal death and one pregnancy termination for multiple malformations.LIMITATIONS, REASONS FOR CAUTIONAs with any review, this review was limited by the quality of the included studies especially in terms of possible methodological limitations, the limited sample size and the retrospective aspect of the studies. Among the 21 selected studies, seven were abstracts and two were case reports. Of the remaining 14 studies, only three were prospective. The tools used in identifying SERa+ oocytes may have varied from one study to another and a consequent misclassification cannot be excluded. Considering the poor resolution of light microscopy in detecting SER aggregates, we are not sure that apparently SERa− oocytes do not really exhibit such a dysmorphism if they were analysed under electronic microscopy or a time lapse system.WIDER IMPLICATIONS OF THE FINDINGSIn the light of the existing data and the lack of a real link between fertilizing SERa+ oocytes and the occurrence of embryo aneuploidy/malformations, we think that discarding SERa+ oocytes may be not the most ethical approach even in patients with large cohorts on the day of oocyte retrieval. Avoiding the wastage of oocytes and embryos with respect to medical ethics remains a constant concern in daily IVF practice. Thus, we recommend that all mature oocytes could be fertilized and embryos originating from SERa− oocytes would be preferably transferred, even if they come from a cohort with SERa+ oocytes. The remaining embryos derived from SERa+ oocytes could be considered with a lower priority for transfer after obtaining consent from the couple if a strict follow-up of the pregnancy and the baby is performed.STUDY FUNDING/COMPETING INTEREST(S)We have no conflict of interest to declare and no funding was received.REGISTRATION NUMBERN/A.
      PubDate: Tue, 26 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez010
      Issue No: Vol. 34, No. 4 (2019)
  • Oxygen concentration alters mitochondrial structure and function in in
           vitro fertilized preimplantation mouse embryos
    • Authors: Belli M; Zhang L, Liu X, et al.
      Pages: 601 - 611
      Abstract: STUDY QUESTIONDoes the oxygen concentration in the culture medium [either physiologic (5%) or atmospheric (20%)] affect mitochondrial ultrastructure and function in preimplantation mouse embryos generated by IVF'SUMMARY ANSWEREmbryos cultured in 20% oxygen show increased mitochondrial abnormalities compared to embryos cultured in 5% oxygen.WHAT IS KNOWN ALREADYART are widely used and have resulted in the birth of more than 8 million children. A variety of media and oxygen concentrations are used to culture embryos. Embryos cultured under physiological O2 tension (5%) reach the blastocyst stage faster and have fewer alterations in gene expression when compared with embryos cultured under atmospheric oxygen conditions (20%). The mechanisms by which oxygen tension affects preimplantation development remain unclear, but mitochondria are believed to play an important role. The aim of this study was to evaluate how mitochondrial ultrastructure and function in IVF embryos were affected by culture under physiologic (5%) or atmospheric (20%) oxygen concentrations.STUDY DESIGN, SIZE, DURATIONZygotes, 2-cell, 4-cell, morula and blastocyst were flushed out of the uterus after natural fertilization and used as controls. IVF was performed in CF1 x B6D2F1 mice and embryos were cultured in Potassium simplex optimized medium (KSOM) with amino acids (KAA) under 5% and 20% O2 until the blastocyst stage. Embryo development with the addition of antioxidants was also tested.PARTICIPANTS/MATERIALS, SETTING, METHODSMitochondrial function was assessed by measuring mitochondrial membrane potential, reactive oxygen species (ROS) production, ATP levels, and the expression of selected genes involved in mitochondrial function. Mitochondria ultrastructure was evaluated by transmission electron microscopy (TEM).MAIN RESULTS AND THE ROLE OF CHANCEEmbryos cultured under 20% O2 had fewer mitochondria and more vacuoles and hooded (abnormal) mitochondria compared to the other groups (P < 0.05). At the blastocyst stage the mitochondria of IVF embryos cultured in 20% O2 had lower mtDNA copy number, a denser matrix and more lamellar cristae than controls. Overall IVF-generated blastocysts had lower mitochondrial membrane potential, higher ROS levels, together with changes in the expression of selected mitochondrial genes (P < 0.05). ATP levels were significantly lower than controls only under 5% O2, with the 20% O2 IVF group having intermediate levels. Unexpectedly, adding antioxidant to the culture medium did not improve development.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONFindings in mice embryos might be different from human embryos.WIDER IMPLICATIONS OF THE FINDINGSThis study suggests that changes in the mitochondria may be part of the mechanism by which lower oxygen concentration leads to better embryo development and further emphasize the importance of mitochondria as a locus of reprogramming.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by R01 HD 082039 to PFR, the Department of Life, Health and Environmental Sciences, University of L’Aquila, Italy (RIA 2016–2018) and the Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, La Sapienza University of Rome, Italy (University grants 2016–2017). The authors declare no competing interests.
      PubDate: Wed, 13 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez011
      Issue No: Vol. 34, No. 4 (2019)
  • Effects of assisted reproductive technologies on transposon regulation in
           the mouse pre-implanted embryo
    • Authors: Carmignac V; Barberet J, Iranzo J, et al.
      Pages: 612 - 622
      Abstract: STUDY QUESTIONDo assisted reproductive technologies (ARTs) impact on the expression of transposable elements (TEs) in preimplantation embryos'SUMMARY ANSWERThe expression of all TE families is globally increased with mouse embryo culture with differences according to culture medium composition.WHAT IS KNOWN ALREADYMammalian genomes are subject to global epigenetic reprogramming during early embryogenesis. Whether ARTs could have consequences on this period of acute epigenetic sensitivity is the matter of intense research. So far, most studies have examined the impact of ARTs on the regulation of imprinted genes. However, very little attention has been given to the control of TEs, which exceed by far the number of genes and account for half of the mammalian genomic mass. This is of particular interest as TEs have the ability to modulate gene structure and expression, and show unique regulatory dynamics during the preimplantation period.STUDY DESIGN, SIZE, DURATIONHere, we evaluated for the first time the impact of ART procedures (superovulation, in-vitro fertilisation and embryo culture) on the control of different TE types throughout preimplantation development of mouse embryos. We also made use of a mouse model carrying a LINE-1 retrotransposition-reporter transgene to follow parental patterns of transmission and mobilisation.PARTICIPANTS/MATERIALS, SETTING, METHODSHybrid B6CBA/F1 mice were used for the expression analyses. Relative TE expression was evaluated by using the nCounter quantification methodology (Nanostring®). This quantitative method allowed us to simultaneously follow 15 TE targets. Another technique of quantification (RTqPCR) was also used.A mouse model carrying a LINE-1 retrotransposition-reporter transgene (LINE-1 GF21) was used to follow parental patterns of transmission and mobilisation.MAIN RESULTS AND THE ROLE OF CHANCEWe found that the superovulation step did not modify the dynamics nor the level of TE transcription across the preimplantation period. However, upon in-vitro culture, TE expression was globally increased at the blastocyst stage in comparison with in-vivo development. Finally, by monitoring the transmission and mobilisation of a transgenic LINE-1 transposon, we found that in-vitro fertilisation may alter the mendelian rate of paternal inheritance.LARGE SCALE DATAN/ALIMITATIONS, REASONS FOR CAUTIONEven though the Nanostring results concerning the dynamics of transcription throughout preimplantation development were based on pools of embryos originating from several females, only two pools were analysed per developmental stage. However, at the blastocyst stage, consistent expressional results were found between the Nanostring technology and the other technique of quantification used, RTqPCR.WIDER IMPLICATIONS OF THE FINDINGSOur findings highlight the sensitivity of TEs to the ART environment and their great potential as biomarkers of culture medium-based effects.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by funding from the ‘Agence de la Biomedecine’, ‘Conseil Régional de Bourgogne’ and ‘RCT grant from INSERM-DGOS’. The authors have no conflicts of interest to declare.
      PubDate: Wed, 13 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez020
      Issue No: Vol. 34, No. 4 (2019)
  • Safety and efficacy of the selective progesterone receptor modulator
           asoprisnil for heavy menstrual bleeding with uterine fibroids: pooled
           analysis of two 12-month, placebo-controlled, randomized trials
    • Authors: Stewart E; Diamond M, Williams A, et al.
      Pages: 623 - 634
      Abstract: STUDY QUESTIONCan asoprisnil, a selective progesterone receptor modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile'SUMMARY ANSWERUninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events.WHAT IS KNOWN ALREADYIn a 3-month study, asoprisnil (5, 10 and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner.STUDY DESIGN, SIZE, DURATIONIn two Phase 3, double-blind, randomized, placebo-controlled, multicentre studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg or placebo (2:2:1) once daily for up to 12 months.PARTICIPANTS/MATERIALS, SETTING, METHODSPremenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N = 907). The primary efficacy endpoint was the percentage of women who met all three predefined criteria at 12 months or the final month for patients who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume and health-related quality of life (HRQL).MAIN RESULTS AND THE ROLE OF CHANCEIn all, 90% and 93% of women in the asoprisnil 10-mg and 25-mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P < 0.001). Similar results were observed at month 6 (P < 0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66–78% in the asoprisnil 10-mg group and 83–93% in the asoprisnil 25-mg group, significantly higher than with placebo (3–12%, P < 0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to −48% and −28%, respectively) and 25 mg (median changes up to −63% and −39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P < 0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by ~2 mm in both asoprisnil groups compared with placebo (P < 0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women.LIMITATIONS, REASONS FOR CAUTIONMost study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects.WIDER IMPLICATIONS OF THE FINDINGSDaily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences.STUDY FUNDING/COMPETING INTEREST(S)This trial was funded by AbbVie Inc. (prior sponsors: TAP Pharmaceutical Products Inc., Abbott Laboratories). E.A. Stewart was a site investigator in the Phase 2 study of asoprisnil and consulted for TAP during the design and conduct of these studies while at Harvard Medical School and Brigham and Women’s Hospital. She received support from National Institutes of Health grants HD063312, HS023418 and HD074711 and research funding, paid to Mayo Clinic for patient care costs related to an NIH-funded trial from InSightec Ltd. She consulted for AbbVie, Allergan, Bayer HealthCare AG, Gynesonics, and Welltwigs. She received royalties from UpToDate and the Med Learning Group. M.P. Diamond received research funding for the conduct of the studies paid to the institution and consulted for AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution from Bayer and ObsEva. A.R.W. Williams consulted for TAP and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr consulted for and received research funding from AbbVie. E.R. Myers consulted for AbbVie, Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie and may own AbbVie stock or stock options. B.M. Schwefel and K...
      PubDate: Wed, 13 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez007
      Issue No: Vol. 34, No. 4 (2019)
  • Activation of the Hippo/TAZ pathway is required for menstrual stem cells
           to suppress myofibroblast and inhibit transforming growth factor β
           signaling in human endometrial stromal cells
    • Authors: Zhu H; Pan Y, Jiang Y, et al.
      Pages: 635 - 645
      Abstract: STUDY QUESTIONCan menstrual stem cells (MenSCs) inhibit myofibroblast differentiation and reverse transforming growth factor β (TGFβ)-mediated activation of myofibroblast phenotypes in human endometrial stromal cells (ESCs)'SUMMARY ANSWERMenSCs suppressed endometrial myofibroblast differentiation and reversed TGFβ-mediated activation of myofibroblast phenotypes, which might be associated with activation of the Hippo/TAZ pathway.WHAT IS KNOWN ALREADYThe potential effect of MenSCs as a cell therapy include attenuation of intrauterine adhesions, but the underlying mechanisms by which MenSCs exerts these effects are not entirely understood.STUDY DESIGN, SIZE, DURATIONWe evaluated the antagonistic effects of MenSCs on myofibroblast differentiation as well as the broader effect of the Hippo/TAZ signaling pathway on TGFβ-mediated induction of myofibroblast gene expression. The study design was based on a cohort of clinical proliferative phase endometrial samples obtained from three healthy premenopausal females with regular menstrual cycles.PARTICIPANTS/MATERIALS, SETTING, METHODSESCs were cocultured with MenSCs or in MenSC-conditioned medium. Fibrotic markers (αSMA, collagen I, CTGF and fibronectin) as well as proliferation and wound-healing abilities were evaluated. Components of the Hippo/TAZ pathway (TAZ, p-TAZ, MOB1, p-MOB1, LATS1 and p-LATS1) were also investigated. Cell Counting Kit 8, wound healing assay, real-time PCR, western blotting, immunofluorescence and shRNA knockdown approaches were used to validate the findings.MAIN RESULTS AND THE ROLE OF CHANCEMenSCs inhibited myofibroblast activation, resulting in more rapid proliferation of ESCs. MenSCs downregulated the expression of myofibroblast markers αSMA and collagen I and promoted endometrial wound healing. Coculture with MenSCs also attenuated the TGFβ-mediated increase in expression of fibrotic marker genes αSMA, collagen I, CTGF and fibronectin, and restored the wound-healing ability inhibited by TGFβ. MenSCs induced Hippo/TAZ pathway activation, resulting in nuclear export and cytoplasmic retention of TAZ. TAZ inhibition was demonstrated to have similar effects even in the absence of MenSCs, and inhibition of TAZ was sufficient to attenuate TGFβ-mediated myofibroblast activation.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThis study included only in vitro experiments. Thus, additional data from in vivo experiments are needed in a future study.WIDER IMPLICATIONS OF THE FINDINGSThe Hippo/TAZ pathway may be an important therapeutic target for endometrial fibrosis.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the National Natural Science Foundation of China (No. 81601236) and Zhejiang Provincial Natural Science Foundation of China (LY19H040009). None of the authors has any competing interests to declare.
      PubDate: Mon, 04 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez001
      Issue No: Vol. 34, No. 4 (2019)
  • Estrogen receptor β upregulates CCL2 via NF-κB signaling in
           endometriotic stromal cells and recruits macrophages to promote the
           pathogenesis of endometriosis
    • Authors: Gou Y; Li X, Li P, et al.
      Pages: 646 - 658
      Abstract: STUDY QUESTIONHow is the activation of estrogen receptor β (ERβ) in endometriotic stromal cells (ESCs) involved in macrophage recruitment to promote the pathogenesis of endometriosis'SUMMARY ANSWERERβ modulates the production of C-C motif chemokine ligand 2 (CCL2) via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in ESCs and thus recruits macrophages to ectopic lesions to promote pathogenesis.WHAT IS KNOWN ALREADYMacrophages are mainly recruited to the peritoneal cavity to promote the pathogenesis of endometriosis. Recent studies have demonstrated that ERβ plays an important role in the progression of endometriosis through modulating apoptosis and inflammation.STUDY DESIGN, SIZE, DURATIONAn observational study consisting of 22 cases (women with endometriosis, diagnosed by laparoscopy and histological analysis) and 14 controls (without endometriosis) was carried out.PARTICIPANTS/MATERIALS, SETTING, METHODSTissues and stromal cells that were isolated from 22 patients with ovarian endometrioma and deeply infiltrating endometriosis were compared with tissues and stromal cells from 14 patients with normal cycling endometrium using immunohistochemistry, quantitative PCR, Western blot, cell migration assay and cloning formation assay. P values < 0.05 were considered significant, and experiments were repeated in at least three different cell preparations.MAIN RESULTS AND THE ROLE OF CHANCEWe observed that accumulated macrophages were recruited to the ectopic milieu and mainly adopted an alternatively activated macrophage (M2) phenotype. To reveal the underlying mechanism for this, we conducted a series of experiments and found that high expression of ERβ led to the production of CCL2 via NF-κB signaling and macrophages were recruited to the ectopic milieu. An in vitro co-culture assay also suggested that the recruited macrophages in turn could promote the proliferation and clonogenic ability of ESCs. Overall, the activation of ERβ in ESCs is involved in macrophage recruitment via NF-κB/CCL2 signaling and subsequently appears to promote the pathogenesis of endometriosis.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONDue to the limitations of obtaining surgical specimens, endometrioma tissues were collected mainly from women diagnosed with middle to late stage endometriosis. We identified the predominant presence of M2 macrophages in the samples used in our study, but the underlying mechanism of how recruited macrophages acquire the M2 phenotype is undefined.WIDER IMPLICATIONS OF THE FINDINGSThis work provides novel insight into the mechanism by which ERβ may modulate macrophage infiltration and promote pathogenesis, which may provide a new therapeutic target for endometriosis.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the National Natural Science Foundation of China (81671430). The authors have no conflicts of interest.
      PubDate: Wed, 06 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez019
      Issue No: Vol. 34, No. 4 (2019)
  • Are interventions in reproductive medicine assessed for plausible and
           clinically relevant effects' A systematic review of power and
           precision in trials and meta-analyses
    • Authors: Stocking K; Wilkinson J, Lensen S, et al.
      Pages: 659 - 665
      Abstract: STUDY QUESTIONHow much statistical power do randomised controlled trials (RCTs) and meta-analyses have to investigate the effectiveness of interventions in reproductive medicine'SUMMARY ANSWERThe largest trials in reproductive medicine are unlikely to detect plausible improvements in live birth rate (LBR), and meta-analyses do not make up for this shortcoming.WHAT IS KNOWN ALREADYEffectiveness of interventions is best evaluated using RCTs. In order to be informative, these trials should be designed to have sufficient power to detect the smallest clinically relevant effect. Similar trials can subsequently be pooled in meta-analyses to more precisely estimate treatment effects.STUDY DESIGN, SIZE, DURATIONA review of power and precision in 199 RCTs and meta-analyses from 107 Cochrane Reviews was conducted.PARTICIPANTS/MATERIALS, SETTING, METHODSSystematic reviews published by Cochrane Gynaecology and Fertility with the primary outcome live birth were identified. For each live birth (or ongoing pregnancy) meta-analysis and for the largest RCT in each, we calculated the power to detect absolute improvements in LBR of varying sizes. Additionally, the 95% CIs of estimated treatment effects from each meta-analysis and RCT were recorded, as these indicate the precision of the result.MAIN RESULTS AND THE ROLE OF CHANCEMedian (interquartile range) power to detect an improvement in LBR of 5 percentage points (pp) (e.g. 25–30%) was 13% (8–21%) for RCTs and 16% (9–33%) for meta-analyses. No RCTs and only 2% of meta-analyses achieved 80% power to detect an improvement of 5 pp. Median power was high (85% for trials and 93% for meta-analyses) only in relation to 20 pp absolute LBR improvement, although substantial numbers of trials and meta-analyses did not achieve 80% power even for this improbably large effect size. Median width of 95% CIs was 25 pp and 21 pp for RCTs and meta-analyses, respectively. We found that 28% of Cochrane Reviews with LBR as the primary outcome contain no live birth (or ongoing pregnancy) data.LARGE-SCALE DATAThe data used in this study may be accessed at'view_only=90f1579ce72747ccbe572992573197bd.LIMITATIONS, REASONS FOR CAUTIONThe design and analysis decisions used in this study are predicted to overestimate the power of trials and meta-analyses, and the size of the problem is therefore likely understated. For some interventions, it is possible that larger trials not reporting live birth or ongoing pregnancy have been conducted, which were not included in our sample. In relation to meta-analyses, we calculated power as though all participants were included in a single trial. This ignores heterogeneity between trials in a meta-analysis, and will cause us to overestimate power.WIDER IMPLICATIONS OF THE FINDINGSTrials capable of detecting realistic improvements in LBR are lacking in reproductive medicine, and meta-analyses are not large enough to overcome this deficiency. This situation will lead to unwarranted pessimism as well as unjustified enthusiasm regarding reproductive interventions, neither of which are consistent with the practice of evidence-based medicine or the idea of informed patient choice. However, RCTs and meta-analyses remain vital to establish the effectiveness of fertility interventions. We discuss strategies to improve the evidence base and call for collaborative studies focusing on the most important research questions.STUDY FUNDING/COMPETING INTEREST(S)There was no specific funding for this study. KS and SL declare no conflict of interest. AV consults for the Human Fertilisation and Embryology Authority (HFEA): all fees are paid directly to AV’s employer. JW declares that publishing research benefits his career. SR is a Statistical Editor for Human Reproduction. JW and AV are Statistical Editors for Cochrane Gynaecology and Fertility. DRB is funded by the NHS as Scientific Director of a clinical IVF service.PROSPERO REGISTRATION NUMBERNone.
      PubDate: Wed, 06 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez017
      Issue No: Vol. 34, No. 4 (2019)
  • A new MEIOB mutation is a recurrent cause for azoospermia and testicular
           meiotic arrest
    • Authors: Gershoni M; Hauser R, Barda S, et al.
      Pages: 666 - 671
      Abstract: STUDY QUESTIONAre there genetic variants that can be used for the clinical evaluation of azoospermic men'SUMMARY ANSWERA novel homozygous frame-shift mutation in the MEIOB gene was identified in three azoospermic patients from two different families.WHAT IS KNOWN ALREADYUp to 1% of all men have complete absence of sperm in the semen, a condition known as azoospermia. There are very few tools for determining the etiology of azoospermia and the likelihood of sperm cells in the testis. The MEIOB gene codes for a single-strand DNA binding protein required for DNA double-strand breaks repair during meiosis. MEIOB appears to be exclusively expressed in human and mouse testis, and MeioB knockout mice are azoospermic due to meiotic arrest.STUDY DESIGN, SIZE, DURATIONTwo brothers with non-obstructive azoospermia (NOA) underwent whole-exome sequencing followed by comprehensive bioinformatics analyses. Candidate variations were further screened in infertile and fertile men, as well as in public and local reference databases.PARTICIPANTS/MATERIALS, SETTING, METHODSThis study included 159 infertile and 77 fertile men. The exomes of two Arab men were completely sequenced. In addition, 213 other men of the same Arab ethnicity (136 infertile and 77 fertile men) underwent restriction fragment length polymorphism (RFLP) screening, as did 21 NOA men, of other ethnicities, with testicular impairment of spermatocyte arrest. All of the infertile men underwent Y-chromosome microdeletion and CFTR gene mutation assessments. Comprehensive bioinformatics analyses were designed to uncover candidate mutations associated with azoospermia.MAIN RESULTS AND THE ROLE OF CHANCEA novel homozygous frame-shift mutation in the MEIOB gene was identified in two brothers of Arab ethnicity. This frame-shift is predicted to result in a truncated MEIOB protein, which lacks the conserved C-terminal DNA binding domain. RFLP screening of the mutation in 157 infertile men, including 112 NOA patients of Arab ethnicity, identified an additional unrelated NOA patient with the same homozygous mutation and a similar testicular impairment. This mutation was not found in available public databases (n > 160 000), nor in the 77 proven fertile men, nor in our database of local Israeli population variations derived from exome and genome sequencing data (n = 500).LIMITATIONS, REASONS FOR CAUTIONWe have thus far screened for only two specific MEIOB probable pathogenic mutations in a relatively small local cohort. Therefore, the relative incidence of MEIOB mutations in azoospermia should be further assessed in larger and diverse cohorts in order to determine the efficiency of MEIOB sequence screening for clinical evaluations.WIDER IMPLICATIONS OF THE FINDINGSThe relatively high incidence of likely NOA-causing mutations in MEIOB that was found in our cohort supports the idea that a complete screening of this gene might be beneficial for clinical evaluation of NOA patients.STUDY FUNDING/COMPETING INTEREST(S)This research was supported in part by a grant to EA from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC grant agreement (616088). There are no competing interests.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Wed, 06 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez016
      Issue No: Vol. 34, No. 4 (2019)
  • Attitudes of anonymous and identity-release oocyte donors towards future
           contact with donor offspring
    • Authors: Miettinen A; Rotkirch A, Suikkari A, et al.
      Pages: 672 - 678
      Abstract: STUDY QUESTIONWhat are the attitudes and expectations of past oocyte donors concerning contact with their donor offspring and contact between donor offspring and their own children'SUMMARY ANSWERThe large majority (95%) of open-identity oocyte donors, as well as voluntarily registered donors (registered before the Finnish 2007 ART law), expressed positive or neutral feelings towards contact with their donor offspring and mainly positive expectations towards contact between donor offspring and their own children.WHAT IS KNOWN ALREADYAlthough there is a growing support for openness and identity-release programmes in gamete donation, there is not much knowledge on how donors feel about potential contact with their offspring. Most previous studies have investigated donor expectations with a relatively short follow-up time, using small samples or participants in voluntary donor linkage services.STUDY DESIGN, SIZE, DURATIONA retrospective cross-sectional survey of all women who had donated oocytes between 1990 and 2012 at three fertility clinics in Finland was carried out in 2013. A self-administered questionnaire was sent out to a total of 569 former oocyte donors.PARTICIPANTS/MATERIALS, SETTING, METHODSIn total, 428 former oocyte donors answered a questionnaire assessing experiences and attitudes related to donation (response rate 75.2%). In this study, 358 donors who were unknown to the recipient were included. The mean follow-up time after the donation was 11.2 years. Before 2008, donors were non-identifiable but could voluntarily consent to release their identifying information to their donor offspring. After 2008, persons born as a result of gamete donation can, from the age of 18, receive information identifying the donor. Altogether 290 respondents had participated in a donation programme in 1990–2007 (before the Finnish ART-law), and 68 participated after the enactment of the ART-law, enabling us to compare attitudes by type of legislation during donation.MAIN RESULTS AND THE ROLE OF CHANCEMost voluntarily registered and open-identity donors welcomed or were neutral to potential contact with their donor offspring but were slightly more cautious towards contact between their own children and a donor-conceived child. Open-end comments revealed some ambiguity and uncertainty as to what to expect from such contact and feelings varied from neutral curiosity and interest to desire to meet the donor-conceived child.LIMITATIONS, REASON FOR CAUTIONIt is not possible to assess whether the opinions of the study participants is representative of all donors in 1990–2012, as 25% of all contacted former donors did not respond to the survey.WIDER IMPLICATIONS OF THE FINDINGSThis study is one of only a few studies among oocyte donors to evaluate long-term psychosocial consequences of the donation and expectations towards contact with donor offspring, using a large sample. Results from this study show that persisting concerns about adverse outcomes of identity release policies are largely unwarranted, but there is a need to develop counselling practices and material for identity-release donors about how to prepare for and adjust to potential contact with donor offspring.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by grants from the Medical Society Life and Health, and from the Otto A. Malm Foundation. The authors have no competing interests to report.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Tue, 26 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez009
      Issue No: Vol. 34, No. 4 (2019)
  • Patients’ attitudes and preferences towards a freeze-all strategy in
           ART treatment
    • Authors: Stormlund S; Schmidt L, Bogstad J, et al.
      Pages: 679 - 688
      Abstract: STUDY QUESTIONWhat are the attitudes towards different aspects of a freeze-all strategy and elective frozen embryo transfer (eFET) in comparison with fresh embryo transfer in assisted reproductive technology treatment among female and male patients before and after their first ART treatment cycle in a public health care setting'SUMMARY ANSWERDespite concerns about the delay in embryo transfer associated with eFET, nearly 60% of the participants were in favor of eFET compared with fresh embryo transfer assuming that the clinical pregnancy rate was equivalent.WHAT IS KNOWN ALREADYVitrification and blastocyst transfer have considerably improved success rates after FET with ongoing pregnancy rates in frozen cycles approaching those seen in fresh treatment cycles. Furthermore, the risk of ovarian hyperstimulation syndrome (OHSS) is essentially eliminated in FET cycles, and FET may be beneficial to the endometrial and fetal development because a hormonal environment mirroring the natural cycle is enabled. However, the freeze-all strategy is not yet implemented as standard care. One reason is the presumption of negative patient attitudes towards a freeze-all embryo strategy. So far, no data regarding patients’ attitudes on a freeze-all strategy have been published.STUDY DESIGN, SIZE, DURATIONThis study was designed as a descriptive cross-sectional study including 165 fertility patients referred for their first ART treatment from December 2014 to June 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSAll newly referred patients participating in a mandatory meeting before initiating ART treatment at the Fertility Clinic, Hvidovre Hospital, Copenhagen, Denmark were requested to fill in an online web-based questionnaire separately for men and women covering attitudes towards a freeze-all strategy, socio-demographic data and reproductive history. The patients were informed about both conventional fresh embryo transfer strategy and the freeze-all strategy prior to answering the questionnaire.MAIN RESULTS AND THE ROLE OF CHANCEThe total response rate was 77.1% (n = 165), and for women and men respectively 85.8 versus 66.0%. The female respondents were significantly more likely to consider the postponement of embryo transfer difficult compared to the male population (78.6 versus 35.5%; P < 0.001) and they were significantly more willing to accept a risk in treatment on own health to achieve a pregnancy than were the male respondents on their partners health (82.5 versus 96.8%; P = 0.025). However, 59.2% of the women and 59.7% of the men agreed that they would choose eFET over fresh embryo transfer if the chance of pregnancy were the same. Most of the patients furthermore agreed that the health of the mother and their baby was of highest importance. In the adjusted analyses we found no significant predictive factors for preferences towards a freeze-all strategy apart from a negative attitude towards delay of transfer in case of previous unsuccessful ART attempts.LIMITATIONS, REASONS FOR CAUTIONSelection bias cannot be excluded, as the total response rate was 77.1%. The hypothetical nature of the items may furthermore limit the validity of the results. In addition, the participants were from a single Fertility Clinic in the Capital Region of Denmark and may therefore not be representative for all fertility patients.WIDER IMPLICATIONS OF THE FINDINGSIn a clinical setting with similar pregnancy rates for eFET and fresh embryo transfer, these results indicate that patients, when given access to information on advantages and disadvantages of both fresh embryo transfer and eFET, are less prone to opt for fresh embryo transfer. This may be ground breaking for a patient-centered paradigm shift in routine ART treatment with a wider implementation of a freeze-all and eFET-strategy eliminating the risk of OHSS.STUDY FUNDING/COMPETING INTEREST(S)The Danish Council for Independent Research and Merck Serono supported the study. The study is part of the Reprounion Collaborative study, co-financed by the European Union, Interreg V ÖKS. No competing interests exist.
      PubDate: Thu, 28 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez006
      Issue No: Vol. 34, No. 4 (2019)
  • Hemodynamic forces enhance decidualization via endothelial-derived
           prostaglandin E2 and prostacyclin in a microfluidic model of the human
    • Authors: Gnecco J; Ding T, Smith C, et al.
      Pages: 702 - 714
      Abstract: STUDY QUESTIONDoes the uterine vasculature play a localized role in promoting stromal cell decidualization in the human endometrium'SUMMARY ANSWEROur study demonstrated that hemodynamic forces induced secretion of specific endothelial cell-derived prostanoids that enhanced endometrial perivascular decidualization via a paracrine mechanism.WHAT IS KNOWN ALREADYDifferentiation of stromal cell fibroblasts into the specialized decidua of the placenta is a progesterone-dependent process; however, histologically, it has long been noted that the first morphological signs of decidualization appear in the perivascular stroma. These observations suggest that the human endometrial vasculature plays an active role in promoting stromal differentiation.STUDY DESIGN, SIZE, DURATIONPrimary human endometrial stromal cells were co-cultured for 14 days with primary uterine microvascular endothelial cells within a microfluidic Organ-on-Chip model of the endometrium.PARTICIPANTS/MATERIALS, SETTING, METHODSCultures were maintained with estradiol and a progestin, with or without continuous laminar perfusion to mimic hemodynamic forces derived from the blood flow. Some cultures additionally received exogenous agonist-mediated challenges. Decidualization in the microfluidic model was assessed morphologically and biochemically. ELISA was used to examine the culture effluent for expression of decidualization markers and prostaglandins. Immunofluorescence was used to monitor cyclooxygenase-2 expression in association with decidualization.MAIN RESULTS AND THE ROLE OF CHANCEA significantly enhanced stromal decidualization response was observed in the co-cultures when the endothelial cells were stimulated with hemodynamic forces (e.g. laminar shear stress) derived from controlled microfluidic perfusion (<0.001). Furthermore, the enhanced progestin-driven stromal differentiation was mediated via cyclooxygenase-2 and the paracrine action of prostaglandin E2 and prostacyclin. Altogether, these translational findings indicate that the vascular endothelium plays a key physiologic role during the early events of perivascular decidualization in the human endometrium.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThis report is largely an in vitro study. Although we were able to experimentally mimic hemodynamic forces in our microfluidic model, we have not yet determined the contribution of additional cell types to the decidualization process or determined the precise physiological rates of shear stress that the microvasculature of the endometrium undergoes in vivo.WIDER IMPLICATIONS OF THE FINDINGSIdentification of specific endothelial-derived prostaglandins and their role during endometrial reproductive processes may have clinical utility as therapeutic targets for reproductive disorders such as infertility, endometriosis, adenomyosis, pre-eclampsia and poor pregnancy outcomes.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the Veterans Affairs (I01 BX002853), the Bill and Melinda Gates Foundation Grand Challenges Exploration (OPP1159411), the Environmental Toxicology Training Grant (NIH T32 ES007028) and the Environmental Protection Agency STAR Center Grant (83573601).CONFLICT OF INTERESTThe authors report no conflicts of interest.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Thu, 21 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez003
      Issue No: Vol. 34, No. 4 (2019)
  • Marijuana smoking and markers of testicular function among men from a
           fertility centre
    • Authors: Nassan F; Arvizu M, Mínguez-Alarcón L, et al.
      Pages: 715 - 723
      Abstract: STUDY QUESTIONIs marijuana smoking associated with semen quality, sperm DNA integrity or serum concentrations of reproductive hormones among subfertile men'SUMMARY ANSWERMen who had ever smoked marijuana had higher sperm concentration and count and lower serum FSH concentrations than men who had never smoked marijuana; no differences were observed between current and past marijuana smokers.WHAT IS KNOWN ALREADYStudies of marijuana abuse in humans and animal models of exposure to marijuana suggest that marijuana smoking adversely impacts spermatogenesis. Data is less clear for moderate consumption levels and multiple studies have found higher serum testosterone concentrations among marijuana consumers.STUDY DESIGN, SIZE, DURATIONThis longitudinal study included 662 subfertile men enroled at the Massachusetts General Hospital Fertility Center between 2000 and 2017. The men provided a total of 1143 semen samples; 317 men also provided blood samples in which we measured reproductive hormones.PARTICIPANTS/MATERIALS, SETTING, METHODSUse of marijuana and other drugs was self-reported at baseline. Standard protocols were followed for measuring semen quality, sex hormones and DNA integrity. We used linear mixed effect models with a random intercept to evaluate the associations of self-reported marijuana smoking at enrolment with semen parameters from subsequently collected samples, and linear regression models for sperm DNA integrity and serum reproductive hormones, while adjusting for confounders including smoking and cocaine use.MAIN RESULTS AND THE ROLE OF CHANCEMen who had ever smoked marijuana (N = 365) had significantly higher sperm concentration (62.7 (95% confidence interval: 56.0, 70.3) million/mL) than men who had never smoked marijuana (N = 297) (45.4 (38.6, 53.3) million/mL) after adjusting for potential confounders (P = 0.0003). There were no significant differences in sperm concentration between current (N = 74) (59.5 (47.3, 74.8) million/mL) and past marijuana smokers (N = 291) (63.5 (56.1, 72.0) million/mL; P = 0.60). A similar pattern was observed for total sperm count. Furthermore, the adjusted prevalence of sperm concentration and total sperm motility below WHO reference values among marijuana smokers was less than half that of never marijuana smokers. Marijuana smokers had significantly lower follicle stimulating hormone (FSH) concentrations than never marijuana smokers (−16% (−27%, −4%)) and there were no significant differences between current and past marijuana smokers (P = 0.53). Marijuana smoking was not associated with other semen parameters, with markers of sperm DNA integrity or with reproductive hormones other than FSH. Chance findings cannot be excluded due to the multiple comparisons.LIMITATIONS, REASONS FOR CAUTIONOur results may not be generalisable to men from the general population. Marijuana smoking was self-reported and there may be misclassification of the exposure.WIDER IMPLICATIONS OF THE FINDINGSThese findings are not consistent with a deleterious effect of marijuana on testicular function. Whether these findings are reflective of the previously described role of the endocannabinoid system in spermatogenesis or a spurious association requires confirmation in further studies.STUDY FUNDING/COMPETING INTEREST(S)The project was funded by grants R01ES009718 and P30ES000002 from the National Institute of Environmental Health Sciences (NIEHS). None of the authors has any conflicts of interest to declare.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Wed, 06 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez002
      Issue No: Vol. 34, No. 4 (2019)
  • Parental time to pregnancy, medically assisted reproduction and pubertal
           development in boys and girls
    • Authors: Ernst A; Lauridsen L, Brix N, et al.
      Pages: 724 - 732
      Abstract: STUDY QUESTIONDoes parental fertility, measured by time to pregnancy (TTP), or use of medically assisted reproduction (MAR) affect pubertal development in the offspring'SUMMARY ANSWERNeither TTP nor type of MAR treatment had clinically relevant implications for mean age at achieving individual pubertal milestones or overall timing of puberty in boys and girls.WHAT IS KNOWN ALREADYParental TTP and MAR have been associated with impaired semen quality in adult sons. Timing of puberty reflects earlier signals of reproductive health, but it remains unclear whether parental fertility or MAR affects pubertal development, especially in the growing generation of children conceived by IVF or ICSI.STUDY DESIGN, SIZE, DURATIONIn this study, 15 819 children born by mothers in the Danish National Birth Cohort from 2000 to 2003 participated in a nationwide puberty cohort (participation rate = 70%). Parental TTP and use of MAR were reported by mothers in early pregnancy and children’s pubertal development data was self-recorded in web-based questionnaires from 11 years of age and 6 monthly throughout puberty (2012–2018).PARTICIPANTS/MATERIALS, SETTING, METHODSPubertal development in children (of planned pregnancies, n = 13 285) born by untreated subfecund (TTP: 6–12 months) (n =2038), untreated severely subfeund (TTP: >12 months) (n = 1242), treated subfecund (n = 230) and treated severely subfecund (n = 1234) parents were compared to children born to more fertile parents (TTP: ≤5 months). We estimated mean monthly differences in mean age at achieving individual pubertal milestones (i.e. age at menarche, voice break, first ejaculation and Tanner stages 2, 3, 4 and 5 for breast or genital development and pubic hair growth) and a combined indicator of timing of puberty. Further, we compared mean age at achieving the individual pubertal milestones in children born by use of IVF or ICSI (n = 480) with children born by controlled ovarian stimulation or ovulation induction with or without intrauterine insemination (n = 902).MAIN RESULTS AND THE ROLE OF CHANCEWe found tendencies towards slightly later mean age at male pubertal timing and slightly earlier mean age at female pubertal timing among children born by untreated subfecund, treated subfecund, untreated severely subfecund and treated severely subfecund parents. There were no specific patterns with increasing TTP, use of MAR nor type of MAR treatment, and the magnitude of the mean differences for individual milestones and overall timing of puberty were small, i.e. 0.9 months (95% CI: −1.0; 2.8) for first ejaculation and −0.5 months (95% CI: −2.0; 1.0) months for age at menarche in boys and girls, respectively, born by treated severely subfecund parents when compared with children born by more fertile parents.LIMITATIONS, REASONS FOR CAUTIONNon-differential misclassification of the self-reported information on parental TTP and pubertal development in the offspring may serve as an alternative explanation of the findings, possibly biasing the estimates towards the null. The information on pubertal development was collected from around 11 years of age and onwards.WIDER IMPLICATIONS OF THE FINDINGSThis study adds to the growing body of literature suggesting only limited harmful effects of parental subfecundity and MAR on offspring’s long-term growth and development.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the Danish Council for Independent Research [DFF 4183-00152]; and the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose.
      PubDate: Tue, 12 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez008
      Issue No: Vol. 34, No. 4 (2019)
  • The risk of birth defects is not associated with semen parameters or mode
           of conception in offspring of men visiting a reproductive health clinic
    • Authors: Pastuszak A; Herati A, Eisenberg M, et al.
      Pages: 733 - 739
      Abstract: STUDY QUESTIONWhat is the relationship between semen parameters and birth defect (BD) rates in offspring of men evaluated for infertility'SUMMARY ANSWERAmong men undergoing infertility evaluation, there is no significant relationship between semen parameters and defect rates in live or still births, even when considering mode of conception.WHAT IS KNOWN ALREADYApproximately 15% of couples have fertility difficulties, with up to a 50% male factor contribution. An increased risk of BDs exists in couples using ART, particularly IVF and ICSI, but it is unknown if this related to the ART procedures or an underlying male factor.STUDY DESIGN, SIZE, DURATIONTo determine if the severity of male factor infertilty, as assessed via sperm quality and mode of conception, is associated with BD rates, we performed a retrospective cohort study. Fathers with semen analysis data in the Baylor College of Medicine Semen Database (BCMSD) were linked with their offspring using Texas Birth Defects Registry (TBDFR) data between 1999 and 2009. In this 10-year period, a total of 1382 men were identified in linkage between the BCMSD and TBDFR. A total of 109 infants with and 2115 infants without BDs were identified.PARTICIPANTS/MATERIALS, SETTING, METHODSTo determine the association between BDs and semen parameters, we used hierarchical linear modeling to determine odds ratios between BD rates, semen parameters, and mode of conception before and after adjustment for paternal, maternal and birth covariates. Semen parameters were stratified based on thresholds defined by the WHO fifth edition laboratory manual for the examination and processing of human semen.MAIN RESULTS AND THE ROLE OF CHANCEIn total 4.9% of 2224 infants were identified with a BD. No statistically significant association was observed between BD rates and semen parameters, before or after adjustment for covariates. The association between sperm concentration and BDs demonstrated an odds ratio (OR) of 1.07 (95% confidence interval: 0.63–1.83); motility: OR 0.91 (0.52–2.22); and total motile count: OR 1.21 (0.70–2.08). Likewise, mode of conception, including infertility treatment and ART, did not affect BD rates (P > 0.05).LIMITATIONS, REASONS FOR CAUTIONBDs recorded in the TBDFR only include live born infants or still births after 20 weeks, our study did not evaluate the effect of impaired semen parameters on developmental defects prior to 20 weeks of gestation. With 109 BDs, our statistical analysis was powered to detect moderate differences associated with particular semen parameters. Additionally, data about mode of conception was not available for 1053 of 2224 births.WIDER IMPLICATIONS OF THE FINDINGSBD rates are not associated with semen quality or mode of conception. The current study suggests that the severity of male factor infertility does not impact the rate of congenital anomalies. This information is important when counseling couples concerned about the relationship between impaired semen quality and BDs.STUDY FUNDING/COMPETING INTEREST(S)Supported in part by the NIH Men’s Reproductive Health Research (MRHR) K12 HD073917 (D.J.L.), the Multidisciplinary K12 Urologic Research (KURe) Career Development Program (D.J.L.), P01HD36289 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development, NIH (D.J.L.), and by U01DD000494 from the Centers for Disease Control and Prevention and the Title V Block Grant to the Texas Department of State Health Services. A.W.P. is a National Institutes of Health K08 Scholar supported by a Mentored Career Development Award (K08DK115835-01) from the from the National Institute of Diabetes and Digestive and Kidney Diseases. This work is also supported in part through a Urology Care Foundation Rising Stars in Urology Award (to A.W.P.) None of the authors has a conflict of interest.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Tue, 12 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez005
      Issue No: Vol. 34, No. 4 (2019)
  • Risk of cancer in children and young adults conceived by assisted
           reproductive technology
    • Authors: Spaan M; van den Belt-Dusebout A, van den Heuvel-Eibrink M, et al.
      Pages: 740 - 750
      Abstract: STUDY QUESTIONDo children conceived by ART have an increased risk of cancer'SUMMARY ANSWEROverall, ART-conceived children do not appear to have an increased risk of cancer.WHAT IS KNOWN ALREADYDespite the increasing use of ART, i.e. IVF or ICSI worldwide, information about possible long-term health risks for children conceived by these techniques is scarce.STUDY DESIGN, SIZE, DURATIONA nationwide historical cohort study with prospective follow-up (median 21 years), including all live-born offspring from women treated with subfertility treatments between 1980 and 2001.PARTICIPANTS/MATERIALS, SETTING, METHODSAll offspring of a nationwide cohort of subfertile women (OMEGA study) treated in one of the 12 Dutch IVF clinics or two fertility clinics. Of 47 690 live-born children, 24 269 were ART-conceived, 13 761 naturally conceived and 9660 were conceived naturally or through fertility drugs, but not by ART. Information on the conception method of each child and potential confounders were collected through the mothers’ questionnaires and medical records. Cancer incidence was ascertained through linkage with The Netherlands Cancer Registry from 1 January 1989 until 1 November 2016. Cancer risk in ART-conceived children was compared with risks in naturally conceived children from subfertile women (hazard ratios [HRs]) and with the general population (standardized incidence ratios [SIRs]).MAIN RESULTS AND THE ROLE OF CHANCEThe median follow-up was 21 years (interquartile range (IQR): 17–25) and was shorter in ART-conceived children (20 years, IQR: 17–23) compared with naturally conceived children (24 years, IQR: 20–30). In total, 231 cancers were observed. Overall cancer risk was not increased in ART-conceived children, neither compared with naturally conceived children from subfertile women (HR: 1.00, 95% CI 0.72–1.38) nor compared with the general population (SIR = 1.11, 95% CI: 0.90–1.36). From 18 years of age onwards, the HR of cancer in ART-conceived versus naturally conceived individuals was 1.25 (95% CI: 0.73–2.13). Slightly but non-significantly increased risks were observed in children conceived by ICSI or cryopreservation (HR = 1.52, 95% CI: 0.81–2.85; 1.80, 95% CI: 0.65–4.95, respectively). Risks of lymphoblastic leukemia (HR = 2.44, 95% CI: 0.81–7.37) and melanoma (HR = 1.86, 95% CI: 0.66–5.27) were non-significantly increased for ART-conceived compared with naturally conceived children.LIMITATIONS, REASONS FOR CAUTIONDespite the large size and long follow-up of the cohort, the number of cancers was rather small for subgroup analyses as cancer in children and young adults is rare.WIDER IMPLICATIONS OF THE FINDINGSOverall, ART-conceived children do not appear to have an increased cancer risk after a median follow-up of 21 years. This large study provides important results, enabling physicians to better inform couples considering ART about the long-term safety of ART for their children. However, larger studies with prolonged follow-up are needed to investigate cancer risk in adults and in children conceived by ICSI and/or from cryopreserved embryos.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by The Dutch Cancer Society (NKI 2006-3631) which funded the OMEGA-women’s cohort and Children Cancer Free (KIKA;147) which funded the OMEGA-offspring cohort. We declare no competing interests.
      PubDate: Mon, 04 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dey394
      Issue No: Vol. 34, No. 4 (2019)
  • Public attitudes towards novel reproductive technologies: a citizens’
           jury on mitochondrial donation
    • Authors: Newson A; de Lacey S, Dowling D, et al.
      Pages: 751 - 757
      Abstract: STUDY QUESTIONDoes an informed group of citizens endorse the clinical use of mitochondrial donation in a country where this is not currently permitted'SUMMARY ANSWERAfter hearing balanced expert evidence and having opportunity for deliberation, a majority (11/14) of participants in a citizens’ jury believed that children should be able to be born using mitochondrial donation.WHAT IS KNOWN ALREADYResearch suggests that patients, oocyte donors and health professionals support mitochondrial donation to prevent transmission of mitochondrial disease. Less is known about public acceptability of this novel reproductive technology, especially from evidence using deliberative methods.STUDY DESIGN, SIZE, DURATIONThis study comprised a citizens’ jury, an established method for determining the views of a well-informed group of community members. The jury had 14 participants, and ran over one and a half days in 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSJurors were members of the public with no experience of mitochondrial disease. They heard and engaged with relevant evidence and were asked to answer the question: ‘Should Australia allow children to be born following mitochondrial donation'’MAIN RESULTS AND THE ROLE OF CHANCEEleven jurors decided that Australia should allow children to be born following mitochondrial donation; 7 of whom added conditions such as the need to limit who can access the intervention. Three jurors decided that children should not (or not yet) be born using this intervention. All jurors were particularly interested in the reliability of evidence, licensing/regulatory mechanisms and the rights of children to access information about their oocyte donors.LIMITATIONS, REASONS FOR CAUTIONJurors’ views were well informed and reflected critical deliberation and discussion, but are not intended to be representative of the whole population.WIDER IMPLICATIONS OF THE FINDINGSWhen presented with high quality evidence, combined with opportunities to undertake structured deliberation of novel reproductive technologies, members of the public are able to engage in detailed discussions. This is the first study to use an established deliberative method to gauge public views towards mitochondrial donation.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by a University of Sydney Industry and Community Collaboration Seed Award (2017), which was awarded contingent on additional funding from the Mito Foundation. Additional funding was provided by the Mito Foundation. The Foundation was not involved in jury facilitation or deliberation, nor analysis of research data.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Wed, 13 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez021
      Issue No: Vol. 34, No. 4 (2019)
  • Extended in vitro culture of human embryos demonstrates the complex nature
           of diagnosing chromosomal mosaicism from a single trophectoderm biopsy
    • Authors: Popovic M; Dhaenens L, Taelman J, et al.
      Pages: 758 - 769
      Abstract: STUDY QUESTIONWhat is the accuracy of preimplantation genetic testing for aneuploidies (PGT-A) when considering human peri-implantation outcomes in vitro'STUDY ANSWERThe probability of accurately diagnosing an embryo as abnormal was 100%, while the proportion of euploid embryos classified as clinically suitable was 61.9%, yet if structural and mosaic abnormalities were not considered accuracy increased to 100%, with a 0% false positive and false negative rate.WHAT IS ALREADY KNOWNEmbryo aneuploidy is associated with implantation failure and early pregnancy loss. However, a proportion of blastocysts are mosaic, containing chromosomally distinct cell populations. Diagnosing chromosomal mosaicism remains a significant challenge for PGT-A. Although mosaic embryos may lead to healthy live births, they are also associated with poorer clinical outcomes. Moreover, the direct effects of mosaicism on early pregnancy remain unknown. Recently, developed in vitro systems allow extended embryo culture for up to 14 days providing a unique opportunity for modelling chromosomal instability during human peri-implantation development.STUDY DESIGN, SIZE, DURATIONA total of 80 embryos were cultured to either 8 (n = 7) or 12 days post-fertilisation (dpf; n = 73). Of these, 54 were PGT-A blastocysts, donated to research following an abnormal (n = 37) or mosaic (n = 17) diagnosis. The remaining 26 were supernumerary blastocysts, obtained from standard assisted reproductive technology (ART) cycles. These embryos underwent trophectoderm (TE) biopsy prior to extended culture.PARTICIPANTS/MATERIALS, SETTING, METHODSWe applied established culture protocols to generate embryo outgrowths. Outgrowth viability was assessed based on careful morphological evaluation. Nine outgrowths were further separated into two or more portions corresponding to inner cell mass (ICM) and TE-derived lineages. A total of 45 embryos were selected for next generation sequencing (NGS) at 8 or 12 dpf. We correlated TE biopsy profiles to both culture outcomes and the chromosomal status of the embryos during later development.MAIN RESULTS AND THE ROLE OF CHANCEOf the 73 embryos cultured to 12 dpf, 51% remained viable, while 49% detached between 8 and 12 dpf. Viable, Day 12 outgrowths were predominately generated from euploid blastocysts and those diagnosed with trisomies, duplications or mosaic aberrations. Conversely, monosomies, deletions and more complex chromosomal constitutions significantly impaired in vitro development to 12 dpf (10% vs. 77%, P < 0.0001). When compared to the original biopsy, we determined 100% concordance for uniform numerical aneuploidies, both in whole outgrowths and in the ICM and TE-derived outgrowth portions. However, uniform structural variants were not always confirmed later in development. Moreover, a high proportion of embryos originally diagnosed as mosaic remained viable at 12 dpf (58%). Of these, 71% were euploid, with normal profiles observed in both ICM and TE-derived lineages. Based on our validation data, we determine a 0% false negative and 18.5% false positive error rate when diagnosing mosaicism. Overall, our findings demonstrate a diagnostic accuracy of 80% in the context of PGT-A. Nevertheless, if structural and mosaic abnormalities are not considered, accuracy increases to 100%, with a 0% false positive and false negative rate.LIMITATIONS REASONS FOR CAUTIONThe inherent limitations of extended in vitro culture, particularly when modelling critical developmental milestones, warrant careful interpretation.WIDER IMPLICATIONS OF THE FINDINGSOur findings echo current prenatal testing data and support the high clinical predictive value of PGT-A for diagnosing uniform numerical aneuploidies, as well as euploid chromosomal constitutions. However, distinguishing technical bias from biological variability will remain a challenge, inherently limiting the accuracy of a single TE biopsy for diagnosing mosaicism.STUDY FUNDING, COMPETING INTEREST(S)This research is funded by the Ghent University Special Research Fund (BOF01D08114) awarded to M.P., the Research Foundation—Flanders (FWO.KAN.0005.01) research grant awarded to B.H. and De Snoo-van’t Hoogerhuijs Stichting awarded to S.M.C.d.S.L. We thank Ferring Pharmaceuticals (Aalst, Belgium) for their unrestricted educational grant. The authors declare no competing interests.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Wed, 06 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez012
      Issue No: Vol. 34, No. 4 (2019)
  • Gonadoblastoma Y locus genes expressed in germ cells of individuals with
           dysgenetic gonads and a Y chromosome in their karyotypes include DDX3Y and
    • Authors: Vogt P; Besikoglu B, Bettendorf M, et al.
      Pages: 770 - 779
      Abstract: STUDY QUESTIONWhich Y genes mapped to the ‘Gonadoblastoma Y (GBY)’ locus on human Y chromosome are expressed in germ cells of individuals with some Differences of Sexual Development (DSD) and a Y chromosome in their karyotype (DSD-XY groups)'SUMMARY ANSWERThe GBY candidate genes DDX3Y and TSPY are expressed in the germ cells of DSD-XY patients from distinct etiologies: patients with mixed gonadal dysgenesis (MGD) and sex chromosome mosaics (45,X0/46,XY; 46,XX/46,XY); patients with complete androgen insensitivity (CAIS), patients with complete gonadal dysgenesis (CGD; e.g. Swyer syndrome).WHAT IS KNOWN ALREADYA GBY locus was proposed to be present on the human Y chromosome because only DSD patients with a Y chromosome in their karyotype have a high—although variable—risk (up to 55%) for germ cell tumour development. GBY was mapped to the proximal part of the short and long Y arm. TSPY located in the proximal part of the short Y arm (Yp11.1) was found to be a strong GBY candidate gene. It is expressed in the germ cells of DSD-XY patients with distinct etiologies but also in foetal and pre-meiotic male spermatogonia. However, the GBY region extends to proximal Yq11 and therefore includes probably more than one candidate gene.STUDY DESIGN, SIZE, DURATIONProtein expression of the putative GBY candidate gene in proximal Yq11, DDX3Y, is compared with that of TSPY in serial gonadal tissue sections of 40 DSD-XY individuals from the three DSD patient groups (MGD, Complete Androgen Insensitivity Syndrome [CAIS], CGD) with and without displaying malignancy. Expression of OCT3/4 in the same tissue samples marks the rate of pluripotent germ cells.PARTICIPANTS/MATERIALS, SETTING, METHODA total of 145 DSD individuals were analysed for the Y chromosome to select the DSD-XY subgroup. PCR multiplex assays with Y gene specific marker set score for putative microdeletions in GBY Locus. Immunohistochemical experiments with specific antisera mark expression of the GBY candidate proteins, DDX3Y, TSPY, in serial sections of the gonadal tissue samples; OCT3/4 expression analyses in parallel reveal the pluripotent germ cell fraction.MAIN RESULTS AND THE ROLE OF CHANCESimilar DDX3Y and TSPY protein expression patterns were found in the germ cells of DSD-XY patients from each subgroup, independent of age. In CAIS patients OCT3/4 expression was often found only in a fraction of these germ cells. This suggest that GBY candidate proteins are also expressed in the non-malignant germ cells of DSD-XY individuals like in male spermatogonia.LIMITATIONS, REASONS FOR CAUTIONVariation of the expression profiles of GBY candidate genes in the germ cells of some DSD-XY individuals suggests distinct transcriptional and translational control mechanisms which are functioning during expression of these Y genes in the DSD-XY germ cells. Their proposed GBY tumour susceptibility function to transform these germ cells to pre-malignant GB/Germ Cell Neoplasia in Situ (GB/GCNIS) cells seems therefore to be limited and depending on their state of pluripotency.WIDER IMPLICATIONS OF THE FINDINGSThese experimental findings are of general importance for each individual identified in the clinic with DSD and a Y chromosome in the karyotype. To judge their risk of germ cell tumour development, OCT3/4 expression analyses on their gonadal tissue section is mandatory to reveal the fraction of germ cells still being pluripotent. Comparative expression analysis of the GBY candidate genes can be helpful to reveal the fraction of germ cells with genetically still activated Y chromosomes contributing to further development of malignancy if at high expression level.STUDY FUNDING/COMPETING INTEREST(S)This research project was supported by a grant (01GM0627) from the BMBF (Bundesministerium für Bildung und Forschung), Germany to P.H.V. and B.B. The authors have no competing interests.
      PubDate: Tue, 12 Feb 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez004
      Issue No: Vol. 34, No. 4 (2019)
  • Erratum. Tracking quality: can embryology key performance indicators be
           used to identify clinically relevant shifts in pregnancy rate'
    • Authors: Hammond E; Morbeck D.
      Pages: 780 - 780
      PubDate: Thu, 31 Jan 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dey395
      Issue No: Vol. 34, No. 4 (2019)
  • Corrigendum. Mitochondrial DNA quantification as a tool for embryo
           viability assessment: retrospective analysis of data from single euploid
           blastocyst transfers
    • Authors: Ravichandran K; McCaffrey C, Grifo J, et al.
      Pages: 781 - 781
      PubDate: Tue, 19 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez013
      Issue No: Vol. 34, No. 4 (2019)
  • Corrigendum. Clinical implications of mitochondrial DNA quantification on
           pregnancy outcomes: a blinded prospective non-selection study
    • Authors: Fragouli E; McCaffrey C, Ravichandran K, et al.
      Pages: 782 - 782
      PubDate: Wed, 13 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez014
      Issue No: Vol. 34, No. 4 (2019)
  • Glycodelin-A stimulates the conversion of human peripheral blood
           CD16−CD56bright NK cell to a decidual NK cell-like phenotype
    • Authors: Lee C; Vijayan M, Wang X, et al.
      Pages: 689 - 701
      Abstract: STUDY QUESTIONDoes glycodelin-A (GdA) induce conversion of human peripheral blood CD16−CD56bright natural killer (NK) cells to decidual NK (dNK) cells to facilitate placentation'SUMMARY ANSWERGdA binds to blood CD16−CD56bright NK cells via its sialylated glycans and converts them to a dNK-like cells, which in turn regulate endothelial cell angiogenesis and trophoblast invasion via vascular endothelial growth factor (VEGF) and insulin-like growth factor-binding protein 1 (IGFBP-1) secretion, respectively.WHAT IS KNOWN ALREADYdNK cells are the most abundant leucocyte population in the decidua. These cells express CD16−CD56bright phenotype. Peripheral blood CD16−CD56bright NK cells and hematopoietic precursors have been suggested to be capable of differentiating towards dNK cells upon exposure to the decidual microenvironment. These cells regulate trophoblast invasion during spiral arteries remodelling and mediate homoeostasis and functions of the endothelial cells. GdA is an abundant glycoprotein in the human decidua with peak expression between the 6th and 12th week of gestation, suggesting a role in early pregnancy. Indeed, GdA interacts with and modulates functions and differentiation of trophoblast and immune cells in the human feto-maternal interface. Aberrant GdA expression during pregnancy is associated with unexplained infertility, pregnancy loss and pre-eclampsia.STUDY DESIGN, SIZE, DURATIONCD16+CD56dim, CD16−CD56bright and dNK cells were isolated from human peripheral blood and decidua tissue, respectively, by immuno-magnetic beads or fluorescence-activated cell sorting. Human extravillous trophoblasts were isolated from first trimester placental tissue after termination of pregnancy. Biological activities of the cells were studied after treatment with GdA at a physiological dose of 5 μg/mL. GdA was purified from human amniotic fluid by immuno-affinity chromatography.PARTICIPANTS/MATERIALS, SETTING, METHODSExpression of VEGF, CD9, CD49a, CD151 and CD158a in the cells were determined by flow cytometry. Angiogenic proteins in the spent media of NK cells were determined by cytokine array and ELISA. Blocking antibodies were used to study the functions of the identified angiogenic proteins. Endothelial cell angiogenesis was determined by tube formation and trans-well migration assays. Cell invasion and migration were determined by trans-well invasion/migration assay. Binding of normal and de-sialylated GdA, and expression of L-selectin and siglec-7 on the NK cells were analysed by flow cytometry. The association between GdA and L-selectin on NK cells was confirmed by immunoprecipitation. Extracellular signal-regulated protein kinases (ERK) activation was determined by Western blotting and functional assays.MAIN RESULTS AND THE ROLE OF CHANCEGdA treatment enhanced the expression of dNK cell markers CD9 and CD49a and the production of the functional dNK secretory product VEGF in the peripheral blood CD16−CD56bright NK cells. The spent media of GdA-treated CD16−CD56bright NK cells promoted tube formation of human umbilical vein endothelial cells and invasiveness of trophoblasts. These stimulatory effects were mediated by the stimulatory activities of GdA on an ERK-activation dependent production of VEGF and IGFBP-1 by the NK cells. GdA had a stronger binding affinity to the CD16−CD56bright NK cells as compared to the CD16+CD56dim NK cells. This GdA-NK cell interaction was reduced by de-sialylation. GdA interacted with L-selectin, expressed only in the CD16−CD56bright NK cells, but not in the CD16+CD56dim NK cells. Anti-L-selectin functional blocking antibody suppressed the binding and biological activities of GdA on the NK cells.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONSome of the above findings are based on a small sample size of peripheral blood CD16−CD56bright NK cells. These results need to be confirmed with human primary dNK cells.WIDER IMPLICATIONS OF THE FINDINGSThis is the first study on the biological role of GdA on conversion of CD16−CD56bright NK cells to dNK-like cells. Further investigation on the glycosylation and functions of GdA will enhance our understanding on human placentation and placenta-associated complications with altered NK cell biology.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the Hong Kong Research Grant Council Grant 17122415, Sanming Project of Medicine in Shenzhen, the Finnish Cancer Foundation, Sigrid Jusélius Foundation and the Finnish Society of Clinical Chemistry. The authors have no competing interests to declare.
      PubDate: Fri, 28 Dec 2018 00:00:00 GMT
      DOI: 10.1093/humrep/dey378
      Issue No: Vol. 34, No. 4 (2018)
School of Mathematical and Computer Sciences
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