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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   (Followers: 1, 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: 54, 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: 89, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 18, SJR: 1.376, CiteScore: 3)
American Entomologist     Full-text available via subscription   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 177, 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: 182, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 195, SJR: 2.713, CiteScore: 3)
American J. of Health-System Pharmacy     Full-text available via subscription   (Followers: 54, SJR: 0.595, CiteScore: 1)
American J. of Hypertension     Hybrid Journal   (Followers: 26, 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: 28, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 17, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 23, 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: 55, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 11, 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: 60, 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: 53, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 345, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 10, 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: 2, 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: 67)
Brain     Hybrid Journal   (Followers: 70, SJR: 5.858, CiteScore: 7)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 49, 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: 38, 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: 603, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 88, 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: 35)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 71, 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: 51, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 23, 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: 23, 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: 25, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 28, 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: 3)
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: 116, SJR: 5.161, CiteScore: 3)
Economic Policy     Hybrid Journal   (Followers: 48, 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: 203, 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: 19, 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: 15, 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: 33, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 14, 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: 34, 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: 3)
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: 6, 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: 15, 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: 75, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 21, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 64, 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: 11)
ILAR J.     Hybrid Journal   (Followers: 3, 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: 10, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 41, 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: 68, 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: 65, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 255, 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: 39, 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: 24, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 50, 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   (Followers: 1)
J. of Burn Care & Research     Hybrid Journal   (Followers: 11, 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: 75  
  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]
  • Editorʼs Choice: Fertility prognosis: a moving target
    • Authors: Lambalk C.
      Abstract: Unexplained subfertility is, by definition, an unsatisfactory diagnosis; indeed, it could be argued that it is not a real 'diagnosis' at all. Instead, it is a situation in time commonly defined as the failure to achieve a clinical pregnancy after at least 12 months of regular unprotected sexual intercourse. This is evidenced by the high rate of natural conception in prolonged follow-up studies of couples with unexplained subfertility. Validated prediction models have been developed from these studies facilitating realistic counselling of couples with unexplained subfertility. These models, which have been applied in a number of countries, are used as decision tools in deciding whether to start fertility treatment or not.
      PubDate: Thu, 06 Jun 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez107
      Issue No: Vol. 34, No. 6 (2019)
  • Thank you to our reviewers – 2018
    • Pages: 959 - 965
      Abstract: We are acutely aware of the importance of high-quality peer review and its role in maintaining and enhancing the scientific quality and clinical relevance of the articles published in Human Reproduction. The journal’s success depends on the many colleagues who take the time to review for us and we could not maintain our position as one of the leading journals in our field without the benefit of their expertise and dedication. For this reason the Editor-in-Chief and the whole editorial team would like to thank all those who reviewed for the journal in 2018. Thank you.
      PubDate: Tue, 21 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez057
      Issue No: Vol. 34, No. 6 (2019)
  • Testicular tissue cryopreservation: 8 years of experience from a
           coordinated network of academic centers
    • Authors: Valli-Pulaski H; Peters K, Gassei K, et al.
      Pages: 966 - 977
      Abstract: STUDY QUESTIONIs it feasible to disseminate testicular tissue cryopreservation with a standardized protocol through a coordinated network of centers and provide centralized processing/freezing for centers that do not have those capabilities'SUMMARY ANSWERCentralized processing and freezing of testicular tissue from multiple sites is feasible and accelerates recruitment, providing the statistical power to make inferences that may inform fertility preservation practice.WHAT IS KNOWN ALREADYSeveral centers in the USA and abroad are preserving testicular biopsies for patients who cannot preserve sperm in anticipation that cell- or tissue-based therapies can be used in the future to generate sperm and offspring.STUDY DESIGN, SIZE, DURATIONTesticular tissue samples from 189 patients were cryopreserved between January 2011 and November 2018. Medical diagnosis, previous chemotherapy exposure, tissue weight, and presence of germ cells were recorded.PARTICIPANTS/MATERIALS, SETTING, METHODSHuman testicular tissue samples were obtained from patients undergoing treatments likely to cause infertility. Twenty five percent of the patient’s tissue was donated to research and 75% was stored for patient’s future use. The tissue was weighed, and research tissue was fixed for histological analysis with Periodic acid-Schiff hematoxylin staining and/or immunofluorescence staining for DEAD-box helicase 4, and/or undifferentiated embryonic cell transcription factor 1.MAIN RESULTS AND THE ROLE OF CHANCEThe average age of fertility preservation patients was 7.9 (SD = 5) years and ranged from 5 months to 34 years. The average amount of tissue collected was 411.3 (SD = 837.3) mg and ranged from 14.4 mg—6880.2 mg. Malignancies (n = 118) were the most common indication for testicular tissue freezing, followed by blood disorders (n = 45) and other conditions (n = 26). Thirty nine percent (n = 74) of patients had initiated their chemotherapy prior to undergoing testicular biopsy. Of the 189 patients recruited to date, 137 have been analyzed for the presence of germ cells and germ cells were confirmed in 132.LIMITATIONS, REASONS FOR CAUTIONThis is a descriptive study of testicular tissues obtained from patients who were at risk of infertility. The function of spermatogonia in those biopsies could not be tested by transplantation due limited sample size.WIDER IMPLICATIONS OF THE FINDINGSPatients and/or guardians are willing to pursue an experimental fertility preservation procedure when no alternatives are available. Our coordinated network of centers found that many patients request fertility preservation after initiating gonadotoxic therapies. This study demonstrates that undifferentiated stem and progenitor spermatogonia may be recovered from the testicular tissues of patients who are in the early stages of their treatment and have not yet received an ablative dose of therapy. The function of those spermatogonia was not tested.STUDY FUNDING/COMPETING INTEREST(S)Support for the research was from the Eunice Kennedy Shriver National Institute for Child Health and Human Development grants HD061289 and HD092084, the Scaife Foundation, the Richard King Mellon Foundation, the Departments of Ob/Gyn & Reproductive Sciences and Urology of the University of Pittsburgh Medical Center, United States-Israel Binational Science Foundation (BSF), and the Kahn Foundation. The authors declare that they do not have competing financial interests.
      PubDate: Tue, 21 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez043
      Issue No: Vol. 34, No. 6 (2019)
  • Sequencing of a ‘mouse azoospermia’ gene panel in azoospermic men:
           identification of RNF212 and STAG3 mutations as novel genetic causes of
           meiotic arrest
    • Authors: Riera-Escamilla A; Enguita-Marruedo A, Moreno-Mendoza D, et al.
      Pages: 978 - 988
      Abstract: STUDY QUESTIONWhat is the diagnostic potential of next generation sequencing (NGS) based on a ‘mouse azoospermia’ gene panel in human non-obstructive azoospermia (NOA)'SUMMARY ANSWERThe diagnostic performance of sequencing a gene panel based on genes associated with mouse azoospermia was relatively successful in idiopathic NOA patients and allowed the discovery of two novel genes involved in NOA due to meiotic arrest.WHAT IS KNOWN ALREADYNOA is a largely heterogeneous clinical entity, which includes different histological pictures. In a large proportion of NOA, the aetiology remains unknown (idiopathic NOA) and yet, unknown genetic factors are likely to play be involved. The mouse is the most broadly used mammalian model for studying human disease because of its usefulness for genetic manipulation and its genetic and physiological similarities to man. Mouse azoospermia models are available in the Mouse Genome Informatics database (MGI: DESIGN, SIZE, DURATIONThe first step was to design of a ‘mouse azoospermia’ gene panel through the consultation of MGI. The second step was NGS analysis of 175 genes in a group of highly selected NOA patients (n = 33). The third step was characterization of the discovered gene defects in human testis tissue, through meiotic studies using surplus testicular biopsy material from the carriers of the RNF212 and STAG3 pathogenic variants. The final step was RNF212 and STAG3 expression analysis in a collection of testis biopsies.PARTICIPANTS/MATERIALS, SETTING, METHODSFrom a total of 1300 infertile patients, 33 idiopathic NOA patients were analysed in this study, including 31 unrelated men and 2 brothers from a consanguineous family. The testis histology of the 31 unrelated NOA patients was as follows: 20 Sertoli cell-only syndrome (SCOS), 11 spermatogenic arrest (6 spermatogonial arrest and 5 spermatocytic arrest). The two brothers were affected by spermatocytic arrest. DNA extracted from blood was used for NGS on Illumina NextSeq500 platform. Generated sequence data was filtered for rare and potentially pathogenic variants. Functional studies in surplus testicular tissue from the carriers included the investigation of meiotic entry, XY body formation and metaphases by performing fluorescent immunohistochemical staining and immunocytochemistry. mRNA expression analysis through RT-qPCR of RNF212 and STAG3 was carried out in a collection of testis biopsies with different histology.MAIN RESULTS AND THE ROLE OF CHANCEOur approach was relatively successful, leading to the genetic diagnosis of one sporadic NOA patient and two NOA brothers. This relatively high diagnostic performance is likely to be related to the stringent patient selection criteria i.e. all known causes of azoospermia were excluded and to the relatively high number of patients with rare testis histology (spermatocytic arrest). All three mutation carriers presented meiotic arrest, leading to the genetic diagnosis of three out of seven cases with this specific testicular phenotype. For the first time, we report biallelic variants in STAG3, in one sporadic patient, and a homozygous RNF212 variant, in the two brothers, as the genetic cause of NOA. Meiotic studies allowed the detection of the functional consequences of the mutations and provided information on the role of STAG3 and RNF212 in human male meiosis.LIMITATIONS, REASONS FOR CAUTIONAll genes, with the exception of 5 out of 175, included in the panel cause azoospermia in mice only in the homozygous or hemizygous state. Consequently, apart from the five known dominant genes, heterozygous variants (except compound heterozygosity) in the remaining genes were not taken into consideration as causes of NOA. We identified the genetic cause in approximately half of the patients with spermatocytic arrest. The low number of analysed patients can be considered as a limitation, but it is a very rare testis phenotype. Due to the low frequency of this specific phenotype among infertile men, our finding may be considered of low clinical impact. However, at an individual level, it does have relevance for prognostic purposes prior testicular sperm extraction.WIDER IMPLICATIONS OF THE FINDINGSOur study represents an additional step towards elucidating the genetic bases of early spermatogenic failure, since we discovered two new genes involved in human male meiotic arrest. We propose the inclusion of RNF212 and STAG3 in a future male infertility diagnostic gene panel. Based on the associated testis phenotype, the identification of pathogenic mutations in these genes also confers a negative predictive value for testicular sperm retrieval. Our meiotic studies provide novel insights into the role of these proteins in human male meiosis. Mutations in STAG3 were first described as a cause of female infertility and ovarian cancer, and Rnf212 knock out in mice leads to male and female infertility. Hence, our results stimulate further research on shared genetic factors causing infertility in both sexes and indicate that genetic counselling should inv...
      PubDate: Fri, 24 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez042
      Issue No: Vol. 34, No. 6 (2019)
  • Comparison of two different oocyte vitrification methods: a prospective,
           paired study on the same genetic background and stimulation protocol
    • Authors: Pujol A; Zamora M, Obradors A, et al.
      Pages: 989 - 997
      Abstract: STUDY QUESTIONCan two different methods for oocyte vitrification, one using an open tool and the other a closed tool, result in similar oocyte survival rates'SUMMARY ANSWERThe oocyte survival rate was found to be higher in the closed method.WHAT IS KNOWN ALREADYOpen vitrification is performed routinely in oocyte donation cycles. Closed oocyte vitrification may result in slower cooling rates and thus it is less used, even though it has been recommended in order to avoid the risk of cross-contamination between material from different patients.STUDY DESIGN, SIZE, DURATIONThis is a prospective cohort study with sibling oocytes carried out in a fertility center between July 2014 and January 2016. The study included 83 oocyte donors each providing a minimum of 12 mature oocytes (metaphase II: MII) at oocyte retrieval. Oocyte survival rate and fertilization rate, as well as reproductive outcomes (biochemical, clinical, ongoing pregnancy and live birth rates) per embryo transfer and also cumulatively between the two methods were compared by Chi2 tests.PARTICIPANTS/MATERIALS, SETTING, METHODSDonor oocytes were denuded and six MII oocytes from each donor were vitrified using an open method and later assigned to one recipient, while another six MII oocytes were vitrified using a closed method and assigned to a different recipient (paired analysis). ICSI was used in all cases and embryo transfer was performed on Day 2–3 in all cases.MAIN RESULTS AND THE ROLE OF CHANCEOocyte donors were 24.8 years old on average (SD 4.7). Recipient age (average 41.2 years, SD 4.7) and BMI (mean 23.8 kg/m2, SD 4.0) were similar between recipient groups. Oocytes vitrified using the closed method had higher survival rate (94.5% versus 88.9%, P = 0.002), but lower fertilization rate (57.1% versus 69.8%, P < 0.001) compared to the open method. The number of fresh embryos transferred in the two groups was 1.8 on average (SD 0.4). Biochemical (45% closed versus 50% open), clinical (40% versus 50%) and ongoing (37.5% versus 42.5%) pregnancy rates were not different between groups (P > 0.05) and neither were live birth rates (37.5% versus 42.5%, P > 0.05). Cumulative reproductive results (obtained after the transfer of all the embryos) were also similar between groups.LIMITATIONS, REASONS FOR CAUTIONThe participants of this study were oocyte donors, i.e. young women in good health, and care should be exerted in extending our results to other populations such as infertility patients, oncofertility patients and women freezing oocytes to delay childbearing.WIDER IMPLICATIONS OF THE FINDINGSOur results suggest that, in spite of different survival and fertilization rates, closed and open oocyte vitrification methods should offer similar reproductive outcomes up to cumulative live birth rates.STUDY FUNDING/COMPETING INTEREST(S)The authors report no conflict of interest. Vitrolife provided the media and the closed method tool needed for the study at no cost.
      PubDate: Wed, 22 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez045
      Issue No: Vol. 34, No. 6 (2019)
  • The clinicians´ dilemma with mosaicism—an insight from inner
           cell mass biopsies
    • Authors: Lawrenz B; El Khatib I, Liñán A, et al.
      Pages: 998 - 1010
      Abstract: STUDY QUESTIONHow reliable are cleavage stage and trophectoderm (TE) biopsies compared to inner cell mass (ICM) biopsies'SUMMARY ANSWERThe reliability of TE biopsy compared to ICM biopsy is almost perfect, but only substantial between cleavage stage biopsy and ICM biopsy.WHAT IS KNOWN ALREADYOne of the prevailing reasons for implantation failure is presumed to be chromosomal aneuploidy in human preimplantation embryos. Preimplantation genetic testing for aneuploidies (PGT-A) has been introduced into assisted reproduction in an effort to increase pregnancy rates. Increasing evidence indicates that genetic results obtained following blastomere or TEbiopsy may not accurately reflect the true genetic status of the embryo due to the presence of embryonic mosaicism, and therefore the reliability of PGT is highly controversial.STUDY DESIGN, SIZE, DURATIONThis was an observational descriptive study, performed in a private infertility centre from August 2016 to January 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSThe mean female age was 33.9 years, ranging from 24 to 46 years, and the mean number of biopsied embryos per couple was 2.2 (range 1–7 embryos). Blastomere biopsies had been performed at cleavage stage on Day 3 (D3) due to the turnover time of genetic testing and the inability to cryopreserve embryos in accordance with the local law governing ART. To confirm the genetic results in embryos not chosen for transfer, additional biopsies of the TE at blastocyst stage (BLASTO–TE) as well as of the ICM (BLASTO–ICM) were performed on D5. Only surplus blastocysts, which had not been selected for transfer and were not cryopreserved in accordance with the law governing ART, had been included.MAIN RESULTS AND THE ROLE OF CHANCEComparison of all biopsies (D3/BLASTO–ICM/BLASTO–TE) per embryo demonstrated that 50 (59.5%) out of 84 embryos showed concordance in all three results (= full concordance). Thirty-four (40.4%) embryos had at least two discordant results between the three biopsies, regardless of whether the embryo diagnosis (aneuploid/euploid) was discordant or not, or in aneuploid embryos, whether the chromosomal patterns were inconsistent. Nine (= 10.7%) embryos had complete discordance between all three biopsies. False positive results between D3/BLASTO–TE, D3/BLASTO–ICM and BLASTO–TE/BLASTO–ICM were 26.4%/30.2% and 7.5%, respectively, while the Kappa agreement between the different approaches was 0.647, 0.553 and 0.857, respectively. Therefore the reliability of D3/BLASTO–TE, D3/BLASTO–ICM and BLASTO–TE/BLASTO–ICM can be interpreted as substantial, as moderate and as almost perfect.LIMITATIONS, REASONS FOR CAUTIONThe limitation of this study is the possible bias in the concordance/discordance rate because embryos that had been selected for transfer did not undergo biopsy on D5.WIDER IMPLICATIONS OF THE FINDINGSThe obvious discordance between the three different approaches for PGT-A underlines the limitations of genetic testing and highlights the importance of ongoing research in order to improve the accuracy of PGT-A results. Until then reproductive specialists will continue to make challenging decisions on whether to transfer or discard an embryo in light of current evidence questioning the reliability of genetic results.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by Igenomix. The funder provided support in the form of salary for R.C. The co-author R.C. is an employee of Igenomix. She participated in the blinded analysis of the samples; however the final data collection and statistical analysis of the results, as well as the decision to publish, was taken by B.L, I.E. and H.F. The authors B.L., I.E., A.L., A.B., A.A., N.D. and H.F. have no competing interests. The funder did not have any additional role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The commercial affiliation of R.C. did not play any role in the study.TRIAL REGISTRATION NUMBERThis study was approved by the Ethics Committee of IVIRMA Middle East Fertility Clinic, Abu Dhabi, UAE (Research Ethics Committee IVI-MEREFA009a/2017).
      PubDate: Wed, 22 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez055
      Issue No: Vol. 34, No. 6 (2019)
  • Deep learning as a predictive tool for fetal heart pregnancy following
           time-lapse incubation and blastocyst transfer
    • Authors: Tran D; Cooke S, Illingworth P, et al.
      Pages: 1011 - 1018
      Abstract: STUDY QUESTIONCan a deep learning model predict the probability of pregnancy with fetal heart (FH) from time-lapse videos'SUMMARY ANSWERWe created a deep learning model named IVY, which was an objective and fully automated system that predicts the probability of FH pregnancy directly from raw time-lapse videos without the need for any manual morphokinetic annotation or blastocyst morphology assessment.WHAT IS KNOWN ALREADYThe contribution of time-lapse imaging in effective embryo selection is promising. Existing algorithms for the analysis of time-lapse imaging are based on morphology and morphokinetic parameters that require subjective human annotation and thus have intrinsic inter-reader and intra-reader variability. Deep learning offers promise for the automation and standardization of embryo selection.STUDY DESIGN, SIZE, DURATIONA retrospective analysis of time-lapse videos and clinical outcomes of 10 638 embryos from eight different IVF clinics, across four different countries, between January 2014 and December 2018.PARTICIPANTS/MATERIALS, SETTING, METHODSThe deep learning model was trained using time-lapse videos with known FH pregnancy outcome to perform a binary classification task of predicting the probability of pregnancy with FH given time-lapse video sequence. The predictive power of the model was measured using the average area under the curve (AUC) of the receiver operating characteristic curve over 5-fold stratified cross-validation.MAIN RESULTS AND THE ROLE OF CHANCEThe deep learning model was able to predict FH pregnancy from time-lapse videos with an AUC of 0.93 [95% CI 0.92–0.94] in 5-fold stratified cross-validation. A hold-out validation test across eight laboratories showed that the AUC was reproducible, ranging from 0.95 to 0.90 across different laboratories with different culture and laboratory processes.LIMITATIONS, REASONS FOR CAUTIONThis study is a retrospective analysis demonstrating that the deep learning model has a high level of predictability of the likelihood that an embryo will implant. The clinical impacts of these findings are still uncertain. Further studies, including prospective randomized controlled trials, are required to evaluate the clinical significance of this deep learning model. The time-lapse videos collected for training and validation are Day 5 embryos; hence, additional adjustment would need to be made for the model to be used in the context of Day 3 transfer.WIDER IMPLICATIONS OF THE FINDINGSThe high predictive value for embryo implantation obtained by the deep learning model may improve the effectiveness of previous approaches used for time-lapse imaging in embryo selection. This may improve the prioritization of the most viable embryo for a single embryo transfer. The deep learning model may also prove to be useful in providing the optimal order for subsequent transfers of cryopreserved embryos.STUDY FUNDING/COMPETING INTEREST(S)D.T. is the co-owner of Harrison AI that has patented this methodology in association with Virtus Health. P.I. is a shareholder in Virtus Health. S.C., P.I. and D.G. are all either employees or contracted with Virtus Health. D.G. has received grant support from Vitrolife, the manufacturer of the Embryoscope time-lapse imaging used in this study. The equipment and time for this study have been jointly provided by Harrison AI and Virtus Health.
      PubDate: Tue, 21 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez064
      Issue No: Vol. 34, No. 6 (2019)
  • Peroxisome proliferator-activated receptor-γ coactivator 1α-mediated
           pathway as a possible therapeutic target in endometriosis
    • Authors: Kataoka H; Mori T, Okimura H, et al.
      Pages: 1019 - 1029
      Abstract: STUDY QUESTIONIs a peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)-mediated pathway involved in the development of endometriosis'SUMMARY ANSWERPGC-1α plays critical roles in inflammation and cell proliferation of endometriotic tissues and may be involved in the development of endometriosis.WHAT IS KNOWN ALREADYExpression levels of PGC-1α are higher in ovarian endometrioma (OE) than normal endometrium (NE). PGC-1α also stimulates aromatase activity and promotes local estrogen biosynthesis in OE.STUDY DESIGN, SIZE, DURATIONThis is a case-controlled biological study using endometrial cells and tissues derived from 23 women with, and 10 women without, OE.PARTICIPANTS/MATERIALS, SETTING, METHODSEctopic endometriotic and eutopic endometrial stromal cells (SCs) were isolated and maintained in culture. PGC-1α was either overexpressed in the cells or knocked down using siRNA. The expression of PGC-1α and other factors during endometriosis was examined using real-time PCR and western blotting, cell proliferation was measured using Cell Counting Kit-8 (WST-8) assays and transcriptional activity was assessed using luciferase reporter assays.MAIN RESULTS AND THE ROLE OF CHANCEPGC-1α overexpression promoted the proliferation of OESCs in a time-dependent manner (P < 0.01 versus control) but not NESCs. PGC-1α stimulated aromatase (P < 0.01 versus control) and interleukin (IL)-6/IL-8 mRNA expression levels (P < 0.05 versus control for each) and led to inhibitor kappa B phosphorylation protein expression and upregulation of the apoptosis inhibitors X-linked inhibitor of apoptosis protein and survivin at mRNA level (P < 0.05 versus control for each). HX531, a selective retinoid-X receptor-α (RXRα) antagonist, suppressed the PGC-1α-induced cell proliferation (P < 0.05 versus control), aromatase/IL-6/IL-8/survivin mRNA expression (P < 0.05 versus control for each) and transcription reporter activity of PGC-1α in a dose-dependent manner (P < 0.01 versus control). Moreover, HX531 downregulated PGC-1α-induced aromatase-promoter PI.3–II transcripts in OESCs, and PGC-1α knockdown reduced aromatase, IL-6/IL-8 and antiapoptotic factors mRNA expression (P < 0.05 versus control for each). Notably, the Histogram score, which was used for quantifying RXRα status, was markedly higher in OE than in NE tissue (P < 0.01).LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONOnly OE tissues were included in this study, while peritoneal and deep infiltrating endometriotic tissues were not. Therefore, these findings might not be generalized to other types of endometriosis.WIDER IMPLICATIONS OF THE FINDINGSIn OESC, PGC-1α stimulated cell proliferation and was involved in local estrogen biosynthesis, inflammation and apoptosis, and these effects of PGC-1α were inhibited by HX531. The suppression of PGC-1α-induced proliferation by HX531 in OESCs but not NESCs suggests that the PGC-1α-RXRα axis could play critical roles in promoting endometriosis. This is the first report of a relationship between PGC-1α and inhibitor of apoptosis proteins in endometriosis. Based on these findings, the PGC-1α-mediated pathway could represent a potential target in molecular therapy of endometriosis.STUDY FUNDING/COMPETING INTEREST(S)The study is supported in part by Grants-in-Aid for Scientific Research (15 K10681 and 15 K10726) from the Ministry of Education, Culture, Sports, Science, and Technology (Japan). The authors have no conflicts of interest to disclose.
      PubDate: Thu, 23 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez067
      Issue No: Vol. 34, No. 6 (2019)
  • Cumulative live birth rates in low-prognosis women
    • Authors: Leijdekkers J; Eijkemans M, van Tilborg T, et al.
      Pages: 1030 - 1041
      Abstract: STUDY QUESTIONDo cumulative live birth rates (CLBRs) over multiple IVF/ICSI cycles confirm the low prognosis in women stratified according to the POSEIDON criteria'SUMMARY ANSWERThe CLBR of low-prognosis women is ~56% over 18 months of IVF/ICSI treatment and varies between the POSEIDON groups, which is primarily attributable to the impact of female age.WHAT IS KNOWN ALREADYThe POSEIDON group recently proposed a new stratification for low-prognosis women in IVF/ICSI treatment, with the aim to define more homogenous populations for clinical trials and stimulate a patient-tailored therapeutic approach. These new criteria combine qualitative and quantitative parameters to create four groups of low-prognosis women with supposedly similar biologic characteristics.STUDY DESIGN, SIZE, DURATIONThis study analyzed the data of a Dutch multicenter observational cohort study including 551 low-prognosis women, aged <44 years, who initiated IVF/ICSI treatment between 2011 and 2014 and were treated with a fixed FSH dose of 150 IU/day in the first treatment cycle.PARTICIPANTS/MATERIALS, SETTING, METHODSLow-prognosis women were categorized into one of the POSEIDON groups based on their age (younger or older than 35 years), anti-Müllerian hormone (AMH) level (above or below 0.96 ng/ml), and the ovarian response (poor or suboptimal) in their first cycle of standard stimulation. The primary outcome was the CLBR over multiple complete IVF/ICSI cycles, including all subsequent fresh and frozen-thawed embryo transfers, within 18 months of treatment. Cumulative incidence curves were obtained using an optimistic and a conservative analytic approach.MAIN RESULTS AND THE ROLE OF CHANCEThe CLBR of the low-prognosis women was on average ~56% over 18 months of IVF/ICSI treatment. Younger unexpected poor (n = 38) and suboptimal (n = 179) responders had a CLBR of ~65% and ~68%, respectively, and younger expected poor responders (n = 65) had a CLBR of ~59%. The CLBR of older unexpected poor (n = 41) and suboptimal responders (n = 102) was ~42% and ~54%, respectively, and of older expected poor responders (n = 126) ~39%. For comparison, the CLBR of younger (n = 164) and older (n = 78) normal responders with an adequate ovarian reserve was ~72% and ~58% over 18 months of treatment, respectively. No large differences were observed in the number of fresh treatment cycles between the POSEIDON groups, with an average of two fresh cycles per woman within 18 months of follow-up.LIMITATIONS, REASONS FOR CAUTIONSmall numbers in some (sub)groups reduced the precision of the estimates. However, our findings provide the first relevant indication of the CLBR of low-prognosis women in the POSEIDON groups. Small FSH dose adjustments between cycles were allowed, inducing therapeutic disparity. Yet, this is in accordance with current daily practice and increases the generalizability of our findings.WIDER IMPLICATIONS OF THE FINDINGSThe CLBRs vary between the POSEIDON groups. This heterogeneity is primarily determined by a woman’s age, reflecting the importance of oocyte quality. In younger women, current IVF/ICSI treatment reaches relatively high CLBR over multiple complete cycles, despite reduced quantitative parameters. In older women, the CLBR remains relatively low over multiple complete cycles, due to the co-occurring decline in quantitative and qualitative parameters. As no effective interventions exist to counteract this decline, clinical management currently relies on proper counselling.STUDY FUNDING/COMPETING INTEREST(S)No external funds were obtained for this study. J.A.L. is supported by a Research Fellowship grant and received an unrestricted personal grant from Merck BV. S.C.O., T.C.v.T., and H.L.T. received an unrestricted personal grant from Merck BV. C.B.L. received research grants from Merck, Ferring, and Guerbet. K.F. received unrestricted research grants from Merck Serono, Ferring, and GoodLife. She also received fees for lectures and consultancy from Ferring and GoodLife. A.H. declares that the Department of Obstetrics and Gynaecology, University Medical Centre Groningen received an unrestricted research grant from Ferring Pharmaceuticals BV, the Netherlands. J.S.E.L. has received unrestricted research grants from Ferring, Zon-MW, and The Dutch Heart Association. He also received travel grants and consultancy fees from Danone, Euroscreen, Ferring, AnshLabs, and Titus Healthcare. B.W.J.M. is supported by an National Health and Medical Research Council Practitioner Fellowship (GNT1082548) and reports consultancy work for ObsEva, Merck, and Guerbet. He also received a research grant from Merck BV and travel support from Guerbet. F.J.M.B. received monetary compensation as a member of the external advisory board for Merck Serono (the Netherlands) and Ferring Pharmaceuticals BV (the Netherlands) for advisory work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development, and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Fri, 24 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez051
      Issue No: Vol. 34, No. 6 (2019)
  • The vaginal microbiome as a predictor for outcome of in vitro
           fertilization with or without intracytoplasmic sperm injection: a
           prospective study
    • Authors: Koedooder R; Singer M, Schoenmakers S, et al.
      Pages: 1042 - 1054
      Abstract: STUDY QUESTIONIs the presence or absence of certain vaginal bacteria associated with failure or success to become pregnant after an in vitro fertilization (IVF) or IVF with intracytoplasmic sperm injection (IVF-ICSI) treatment'SUMMARY ANSWERMicrobiome profiling with the use of interspace profiling (IS-pro) technique enables stratification of the chance of becoming pregnant prior to the start of an IVF or IVF-ICSI treatment.WHAT IS KNOWN ALREADYLive-birth rates for an IVF or IVF-ICSI treatment vary between 25 and 35% per cycle and it is difficult to predict who will or will not get pregnant after embryo transfer (ET). Recently, it was suggested that the composition of the vaginal microbiota prior to treatment might predict pregnancy outcome. Analysis of the vaginal microbiome prior to treatment might, therefore, offer an opportunity to improve the success rate of IVF or IVF-ICSI.STUDY DESIGN, SIZE, DURATIONIn a prospective cohort study, 303 women (age, 20–42 years) undergoing IVF or IVF-ICSI treatment in the Netherlands were included between June 2015 and March 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSStudy subjects provided a vaginal sample before the start of the IVF or IVF-ICSI procedure. The vaginal microbiota composition was determined using the IS-pro technique. IS-pro is a eubacterial technique based on the detection and categorization of the length of the 16S–23S rRNA gene interspace region. Microbiome profiles were assigned to community state types based on the dominant bacterial species. The predictive accuracy of the microbiome profiles for IVF and IVF-ICSI outcome of fresh ET was evaluated by a combined prediction model based on a small number of bacterial species. From this cohort, a model was built to predict outcome of fertility treatment. This model was externally validated in a cohort of 50 women who were undergoing IVF or IVF-ICSI treatment between March 2018 and May 2018 in the Dutch division of the MVZ VivaNeo Kinderwunschzentrum Düsseldorf, Germany.MAIN RESULTS AND THE ROLE OF CHANCEIn total, the vaginal microbiota of 192 women who underwent a fresh ET could be analysed. Women with a low percentage of Lactobacillus in their vaginal sample were less likely to have a successful embryo implantation. The prediction model identified a subgroup of women (17.7%, n = 34) who had a low chance to become pregnant following fresh ET. This failure was correctly predicted in 32 out of 34 women based on the vaginal microbiota composition, resulting in a predictive accuracy of 94% (sensitivity, 26%; specificity, 97%). Additionally, the degree of dominance of Lactobacillus crispatus was an important factor in predicting pregnancy. Women who had a favourable profile as well as <60% L. crispatus had a high chance of pregnancy: more than half of these women (50 out of 95) became pregnant. In the external validation cohort, none of the women who had a negative prediction (low chance of pregnancy) became pregnant.LIMITATIONS, REASONS FOR CAUTIONBecause our study uses a well-defined study population, the results will be limited to the IVF or IVF-ICSI population. Whether these results can be extrapolated to the general population trying to achieve pregnancy without ART cannot be determined from these data.WIDER IMPLICATIONS OF THE FINDINGSOur results indicate that vaginal microbiome profiling using the IS-pro technique enables stratification of the chance of becoming pregnant prior to the start of an IVF or IVF-ICSI treatment. Knowledge of their vaginal microbiota may enable couples to make a more balanced decision regarding timing and continuation of their IVF or IVF-ICSI treatment cycles.STUDY FUNDING/COMPETING INTEREST(S)This study was financed by NGI Pre-Seed 2014–2016, RedMedTech Discovery Fund 2014–2017, STW Valorisation grant 1 2014–2015, STW Take-off early phase trajectory 2015–2016 and Eurostars VALBIOME grant (reference number: 8884). The employer of W.J.S.S.C. has in collaboration with ARTPred acquired a MIND subsidy to cover part of the costs of this collaboration project. The following grants are received but not used to finance this study: grants from Innovatie Prestatie Contract, MIT Haalbaarheid, other from Dutch R&D tax credit WBSO, RedMedTech Discovery Fund, (J.D.d.J.). Grants from Ferring (J.S.E.L., K.F., C.B.L. and J.M.J.S.S.), Merck Serono (K.F. and C.B.L.), Dutch Heart Foundation (J.S.E.L.), Metagenics Inc. (J.S.E.L.), GoodLife (K.F.), Guerbet (C.B.L.). R.K. is employed by ARTPred B.V. during her PhD at Erasmus Medical Centre (MC). S.A.M. has a 100% University appointment. I.S.P.H.M.S., S.A.M. and A.E.B. are co-owners of IS-Diagnostics Ltd. J.D.d.J. is co-owner of ARTPred B.V., from which he reports personal fees. P.H.M.S. reports non-financial support from ARTPred B.V. P.H.M.S., J.D.d.J. and A.E.B. have obtained patents `Microbial population analysis’ (9506109) and `Microbial population analysis’ (20170159108), both licenced to ARTPred B.V. J.D.d.J. and A.E.B. report patent applications `Method and kit for predicting the outcome of an assisted reproductive technology procedure’ (392EPP0) and patent `Method and kit for altering the outcome of an assisted reproductive technology procedure’ by ARTPred. W.J.S.S.C. received personal consultancy and educational fees from Goodlife Fertility B.V. J.S.E.L. reports personal consultancy fees from ARTPred B.V., Titus Heal...
      PubDate: Thu, 23 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez065
      Issue No: Vol. 34, No. 6 (2019)
  • The effectiveness and safety of in vitro maturation of oocytes versus in
           vitro fertilization in women with a high antral follicle count
    • Authors: Ho V; Braam S, Pham T, et al.
      Pages: 1055 - 1064
      Abstract: STUDY QUESTIONWhat is the effectiveness and safety of IVM compared with IVF for the treatment of women with high antral follicle count (AFC)'SUMMARY ANSWERIn women with high AFC undergoing assisted reproductive technique (ART), IVM is an effective alternative compared with IVF, while it eliminates the risk of ovarian hyperstimulation syndrome (OHSS).WHAT IS KNOWN ALREADYIVM is postulated to be an alternative to conventional IVF to avoid OHSS. It has particular potential in women with high AFC who are known to be at increased risk of OHSS. To date, IVM and IVF have only been compared in small cohort studies.STUDY DESIGN, SIZE AND DURATIONWe performed a retrospective cohort study including 919 women, of whom 608 underwent IVM and 311 IVF. The treatments were conducted at IVFMD, My Duc Hospital, Ho Chi Minh, Vietnam, from July 2015 to December 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSWe studied infertile women aged 18–38 years with an indication for ART and with an AFC ≥24. Women received either IVM or IVF treatment depending on patient’s or physician’s preference. In IVM cycles, women received 3 days of FSH 100 IU/day followed by hCG 10 000 IU. In IVF cycles, women underwent a gonadotropin-releasing hormone antagonist protocol and were triggered with hCG 6500 IU. Outcome measures were live birth rate (LBR) after first embryo transfer and cumulative LBR after one complete cycle, defined as the chance of having live birth after all fresh and frozen transfers of embryos derived from one IVM/IVF cycle. We also report on clinical pregnancy, miscarriage, multiple pregnancy and OHSS.MAIN RESULTS AND THE ROLE OF CHANCEBaseline characteristics including age and BMI were comparable between groups. In the IVM group (608 started cycles), there were 511 fresh and 167 frozen transfers. In the IVF group (311 started cycles), there were 209 fresh and 185 frozen transfers. The number of mature oocytes, embryos, good embryos and frozen embryos was significantly lower in the IVM compared with the IVF group. LBRs after the first transfer were 222/608 (36.5%) versus 127/311 (40.8%) (adjusted odds ratio [OR], 0.74; 95% confidence interval [CI], 0.42–1.30). Cumulative LBRs after one completed cycle were 239/608 (39.3%) versus 155/311 (49.8%) (adjusted OR, 0.52; 95% CI, 0.30–0.89). OHSS did not occur in the IVM group versus 11/311 (3.5%) in the IVF group.LIMITATIONS AND REASONS FOR CAUTIONOur study is limited by its non-randomized design. Randomized clinical trials are required to precisely compare the outcomes after IVM versus IVF.WIDER IMPLICATIONS OF THE FINDINGSIn infertile women with a high AFC, IVM is a feasible alternative to standard IVF that markedly reduces OHSS and is potentially more patient friendly and cost effective.STUDY FUNDING/COMPETING INTEREST(S)No external funding was sought to support this work. B.W.M. is supported by a National Health Medical Research Council Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. All other authors have no conflicts of interest.TRIAL REGISTRATION NUMBERNA
      PubDate: Tue, 21 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez060
      Issue No: Vol. 34, No. 6 (2019)
  • Infertility-related distress and female sexual function during assisted
    • Authors: Facchin F; Somigliana E, Busnelli A, et al.
      Pages: 1065 - 1073
      Abstract: STUDY QUESTIONIs infertility-related distress a risk factor for impaired female sexual function in women undergoing assisted reproduction'SUMMARY ANSWERInfertility-related distress, and especially social, sexual, and relationship concerns, is associated with female sexual dysfunction.WHAT IS KNOWN ALREADYWomen with infertility are more likely to present sexual dysfunction relative to those without infertility. Moreover, assisted reproduction is associated with increased risk for female sexual problems. To date, this higher proportion of sexual impairment in infertile women has been simplistically linked to the stress associated with the condition and investigated risk factors included mainly demographic and clinical variables. Quantitative studies aimed at identifying risk factors for sexual dysfunction that also included the evaluation of infertility-related distress are conversely lacking.STUDY DESIGN, SIZE, DURATIONThis observational study was conducted at the Infertility Unit of the Fondazione Ca’ Granda, Ospedale Maggiore Policlinico of Milan between 2017 and 2018.PARTICIPANTS/MATERIALS, SETTING, METHODSWe included 269 consecutive patients with infertility aged 24–45 (37.8 ± 4.0 years). Sexual function outcomes were sexual dysfunction (assessed with the Female Sexual Function Index), sexual distress (evaluated with the Female Sexual Distress Scale-Revised), dyspareunia, and number of intercourses in the month preceding ovarian stimulation. Infertility-related distress was measured with the Fertility Problem Inventory (FPI). The effects of potential confounders such as demographic variables (women’s and partners’ age and level of education) and infertility-related factors (type and cause of infertility, number of previous IVF cycles, and duration of infertility) were also examined.MAIN RESULTS AND THE ROLE OF CHANCEWomen with higher infertility-related distress were more likely to report sexual dysfunction (odds ratio = 1.02 per point of score; 95% CI, 1.01–1.03; P = 0.001). Three FPI domains (i.e. social, relational, and sexual concerns) were correlated with almost all sexual function outcomes (Ps < 0.05).LIMITATIONS, REASONS FOR CAUTIONWomen who were not sexually active were not included, thus reasons for sexual inactivity should be further explored in future studies. Data regarding men (e.g. sexual function and infertility-related distress) were lacking, thus cross-partner effects were not examined. Recall bias (also due to the fact that questionnaires were administered on the day of oocytes retrieval) and social desirability bias may have also affected women’s responses to the questionnaires.WIDER IMPLICATIONS OF THE FINDINGSSocial, relational, and sexual concerns should be assessed and addressed in psychological counselling with the infertile couple.STUDY FUNDING/COMPETING INTEREST(S)None.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Wed, 15 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez046
      Issue No: Vol. 34, No. 6 (2019)
  • Professionals’ barriers in female oncofertility care and strategies
           for improvement
    • Authors: van den Berg M; Baysal Ö, Nelen W, et al.
      Pages: 1074 - 1082
      Abstract: STUDY QUESTIONWhat are healthcare professionals’ barriers and strategies for improvement in female oncofertility care'SUMMARY ANSWERProfessionals perceived barriers in knowledge, attitude and organization of oncofertility care and suggested strategies to improve oncofertility care.WHAT IS KNOWN ALREADYThe potential loss of fertility is one of the most important undesirable side effects of cancer treatment in women of reproductive age. Unfortunately, despite guideline recommendations, not all patients are informed about their fertility risks and referred for fertility preservation (FP) counselling. Insight into barriers for discussing FP and appropriate referral is necessary before improvements can be made.STUDY DESIGN, SIZE, DURATIONThe aim of this was study was to identify barriers and gather improvement suggestions through semi-structured in-depth interviews conducted with 24 professionals working in oncofertility care. Subsequently, an expert panel meeting was held to reach consensus on a set of improvement strategies.PARTICIPANTS/MATERIALS, SETTING, METHODSOncological professionals were recruited from the three Dutch expertise hospitals for female FP and their affiliated hospitals. The expert panel consisted of six healthcare professionals, five survivors and two researchers. In the Dutch setting, financial aspects do not play a role in oncofertility care.MAIN RESULTS AND THE ROLE OF CHANCE Barriers were identified and categorized into the patient level (e.g. focus on surviving cancer), the professional level (e.g. lack of awareness, knowledge, time, and attitude), or the organizational level (e.g. unavailable written information, disagreement on who is responsible for discussing infertility risks). The expert panel reached consensus on essential elements for a multifaceted improvement programme: development of information materials (leaflets, online decision aid), education of professionals, a role for specialized oncology nurses in informing patients and patient navigators at the fertility department to facilitate referral and counselling, medical record reminders, standard consultations with a gynaecologist and agreement on responsibility.LIMITATIONS, REASONS FOR CAUTIONSelection bias could have occurred because it is likely that only professionals with interest in oncofertility care participated. However, this would mean that the barriers were underestimated.WIDER IMPLICATIONS OF THE FINDINGSThis study forms the basis for the development of a multifaceted oncofertility programme, which is essential to increase adherence to the national clinical guideline.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the Radboud university medical center. The authors have declared no competing interests. Prof. Dr Braat reports unrestricted grants from Ferring BV, Serono and Goodlife, outside the submitted work.TRIAL REGISTRATION NUMBERN/A
      PubDate: Tue, 21 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez062
      Issue No: Vol. 34, No. 6 (2019)
  • Impact of cancer chemotherapy before ovarian cortex cryopreservation on
           ovarian tissue transplantation
    • Authors: Poirot C; Fortin A, Lacorte J, et al.
      Pages: 1083 - 1094
      Abstract: STUDY QUESTIONHow efficacious is transplantation of ovarian cortex previously exposed to chemotherapy'SUMMARY ANSWERPrior exposure to chemotherapy did not disrupt the function of cryopreserved ovarian tissue after transplantation.WHAT IS KNOWN ALREADYOvarian tissue cryopreservation (OTC) followed by ovarian tissue transplantation (OTT) is an efficacious technique for restoration of female fertility. At least 130 children have been born following this procedure. To date, little is known about the efficacy of OTT in patients exposed to cancer chemotherapy prior to OTC.STUDY DESIGN, SIZE, DURATIONThis study evaluates the recovery of ovarian function and fertility in 31 consecutive patients who had received OTT, between 2005 and 2015.PARTICIPANTS/MATERIALS, SETTING, METHODSThirty one patients, wanting children, were transplanted with autologous ovarian cortex, among which 22 patients (71%) had been exposed to chemotherapy before OTC. Recovery of ovarian function was considered total once menstruation occurred. Ovarian function recovery (OFR), ovarian graft survival, and incidence of pregnancy were related to previous chemotherapy exposure, type of chemotherapy and graft characteristics (number of grafted fragments and follicular density).MAIN RESULTS AND ROLE OF CHANCEThe amount of ovarian tissue collected was the only parameter to show any significant change between patients with versus without previous chemotherapy. At 1 year after OTT, the cumulative incidence of OFR was 83% (93% in patients exposed to chemotherapy and 67% in others (P = 0.14)). A low follicular density (<0.3 foll/mm2) in the transplant and a low number of grafted fragments (<16) were significantly associated with a delayed OFR. Graft survival at 2 years after OTT was 77%. It was significantly lower in patients exposed to bifunctional alkylating agents before ovarian cryopreservation and in patients with a low follicular density. The proportion of women who succeeded in having at least one live birth was 23% in the total population, 0% (0/9) in the group ‘no previous chemotherapy’, and 32% (7/22) in the group ‘previous chemotherapy’. The cumulative incidence of pregnancy (Kaplan–Meier) at 3 years after OTT was 36% overall and 49% in case of previous chemotherapy, with no difference related to previous chemotherapy exposure. In total there were 13 pregnancies and 8 births in 7 patients.LIMITATIONS, REASONS FOR CAUTIONThe pathology in the two groups of patients was not comparable. In the group of patients who had chemotherapy before OTC, there were 95% of hematological malignancies. In the group of patients who did not have chemotherapy before OTC only 1 out of 9 patients had a malignant hematological disease while 44% had some pathology affecting the ovaries. Few women are available for study and only large changes are likely to have statistical significance.WIDER IMPLICATIONS OF THE FINDINGSThese results suggest that prior cancer chemotherapy should no longer be considered a limitation to cryopreservation of ovarian tissue and current recommendations in this regard should be revised.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the Agence de la Biomédecine (France’s biomedical office). There are no competing interests to report.TRIAL REGISTRATION NUMBERNCT02184806.
      PubDate: Wed, 22 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez047
      Issue No: Vol. 34, No. 6 (2019)
  • Altered cytoplasmic maturation in rescued in vitro matured oocytes
    • Authors: Ferrer-Vaquer A; Barragán M, Rodríguez A, et al.
      Pages: 1095 - 1105
      Abstract: ABSTRACTSTUDY QUESTIONDo culture conditions affect cytoplasmic maturation in denuded immature non-GV oocytes'SUMMARY ANSWERThe maturation rate of denuded non-GV oocytes is not affected by culture media, but in vitro maturation seems to alter the mitochondrial membrane potential, endoplasmic reticulum (ER) and actin cytoskeleton compared with in vivo maturation.WHAT IS KNOWN ALREADYIn vitro maturation of denuded immature non-GV oocytes benefits cycles with poor in vivo MII oocyte collection, but maturation levels of non-GV oocytes are only scored by polar body extrusion. Since oocyte maturation involves nuclear as well as cytoplasmic maturation for full meiotic competence, further knowledge is needed about cytoplasmic maturation in in vitro culture.STUDY DESIGN, SIZE, DURATIONThis basic research study was carried out between January 2017 and September 2018.PARTICIPANTS/MATERIALS, SETTING, METHODSA total of 339 denuded immature non-GV oocytes were cultured in SAGE 1-Step (177) or G-2 PLUS (162) for 6–8 h after retrieval, and 72 in vivo matured MII oocytes were used as controls. Cultured immature non-GV oocytes were scored for polar body extrusion and analysed for mitochondrial membrane potential (ΔΨm), ER clusters, cortical granules number and distribution, spindle morphology and actin cytoskeleton organization. The obtained parameter values were compared to in vivo matured MII oocyte parameter values.MAIN RESULTS AND THE ROLE OF CHANCEThe maturation rates of oocytes cultured in G-2 PLUS and SAGE 1-Step were similar (65% vs 64.2%; P = 0.91). The differences observed in cortical granule density were not statistically significant. Also spindle morphometric parameters were mostly similar between in vitro and in vivo matured MII oocytes. However, the number of ER clusters, the ΔΨm and the cortical actin thickness showed significant differences between in vivo MII oocytes and denuded immature non-GV oocytes cultured in vitro until meiosis completion.LIMITATIONS, REASONS FOR CAUTIONFrozen-thawed oocytes together with fresh oocytes were used as controls. Due to technical limitations (fixation method and fluorochrome overlap), only one or two parameters could be studied per oocyte. Thus, a global view of the maturation status for each individual oocyte could not be obtained.WIDER IMPLICATIONS OF THE FINDINGSCharacterization of in vitro matured oocytes at the cellular level will help us to understand the differences observed in the clinical outcomes reported with rescue IVM compared to in vivo MII oocytes and to improve the culture methods applied.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by intramural funding of Clinica Eugin and by the Torres Quevedo Program to A.F.-V. from the Spanish Ministry of Economy and Competitiveness. No competing interests are declared.
      PubDate: Thu, 23 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez052
      Issue No: Vol. 34, No. 6 (2019)
  • Antibiotic therapy with metronidazole reduces endometriosis disease
           progression in mice: a potential role for gut microbiota
    • Authors: Chadchan S; Cheng M, Parnell L, et al.
      Pages: 1106 - 1116
      Abstract: STUDY QUESTIONDoes altering gut microbiota with antibiotic treatment have any impact on endometriosis progression'SUMMARY ANSWERAntibiotic therapy reduces endometriosis progression in mice, possibly by reducing specific gut bacteria.WHAT IS KNOWN ALREADYEndometriosis, a chronic condition causing abdominal pain and infertility, afflicts up to 10% of women between the ages of 25 and 40, ~5 million women in the USA. Current treatment strategies, including hormone therapy and surgery, have significant side effects and do not prevent recurrences. We have little understanding of why some women develop endometriosis and others do not.STUDY DESIGN, SIZE, DURATIONMice were treated with broad-spectrum antibiotics or metronidazole, subjected to surgically-induced endometriosis and assayed after 21 days.PARTICIPANTS/MATERIALS, SETTING, METHODSThe volumes and weights of endometriotic lesions and histological signatures were analysed. Proliferation and inflammation in lesions were assessed by counting cells that were positive for the proliferation marker Ki-67 and the macrophage marker Iba1, respectively. Differences in faecal bacterial composition were assessed in mice with and without endometriosis, and faecal microbiota transfer studies were performed.MAIN RESULTS AND THE ROLE OF CHANCEIn mice treated with broad-spectrum antibiotics (vancomycin, neomycin, metronidazole and ampicillin), endometriotic lesions were significantly smaller (~ 5-fold; P < 0.01) with fewer proliferating cells (P < 0.001) than those in mice treated with vehicle. Additionally, inflammatory responses, as measured by the macrophage marker Iba1 in lesions and IL-1β, TNF-α, IL-6 and TGF-β1 in peritoneal fluid, were significantly reduced in mice treated with broad-spectrum antibiotics (P < 0.05). In mice treated with metronidazole only, but not in those treated with neomycin, ectopic lesions were significantly (P < 0.001) smaller in volume than those from vehicle-treated mice. Finally, oral gavage of faeces from mice with endometriosis restored the endometriotic lesion growth and inflammation (P < 0.05 and P < 0.01, respectively) in metronidazole-treated mice.LARGE-SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThese findings are from a mouse model of surgically-induced endometriosis. Further studies are needed to determine the mechanism by which gut bacteria promote inflammation, identify bacterial genera or species that promote disease progression and assess the translatability of these findings to humans.WIDER IMPLICATIONS OF THE FINDINGSOur findings suggest that gut bacteria promote endometriosis progression in mice. This finding if translated to humans, could aid in the development of improved diagnostic tools and personalised treatment strategies.STUDY FUNDING AND COMPETING INTEREST(S)This work was funded, in part, by: a National Institutes of Health (NIH)/ National Institute of Child Health and Human Development (NICHD) grant (R00HD080742) to RK; Washington University School of Medicine start-up funds to RK; an Endometriosis Foundation of America Research Award to R.K.; and an NIH/NICHD grant (R01HD091218) to IUM. The authors report no conflict of interest.
      PubDate: Tue, 30 Apr 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez041
      Issue No: Vol. 34, No. 6 (2019)
  • Low prevalence of male microchimerism in women with
           Mayer–Rokitansky–Küster–Hauser syndrome
    • Authors: Peters H; Johnson B, Ehli E, et al.
      Pages: 1117 - 1125
      Abstract: STUDY QUESTIONIs there an increased prevalence of male microchimerism in women with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives'SUMMARY ANSWERPredominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism.WHAT IS KNOWN ALREADYThe etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences.STUDY DESIGN, SIZE, DURATIONAn observational case–control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients’ association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant.PARTICIPANTS/MATERIALS, SETTING, METHODSAfter written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome–specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data.MAIN RESULTS AND THE ROLE OF CHANCEThe final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59–21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse.LIMITATIONS, REASON FOR CAUTIONWe are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection.WIDER IMPLICATIONS OF THE FINDINGSThis is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells.STUDY FUNDING/COMPETING INTEREST(S)None.TRIAL REGISTRATION NUMBERDutch trial register, NTR5961.
      PubDate: Tue, 21 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez044
      Issue No: Vol. 34, No. 6 (2019)
  • Predicting the chances of having a baby with or without treatment at
           different time points in couples with unexplained subfertility
    • Authors: McLernon D; Lee A, Maheshwari A, et al.
      Pages: 1126 - 1138
      Abstract: STUDY QUESTIONCan we develop a prediction model that can estimate the chances of conception leading to live birth with and without treatment at different points in time in couples with unexplained subfertility'SUMMARY ANSWERYes, a dynamic model was developed that predicted the probability of conceiving under expectant management and following active treatments (in vitro fertilisation (IVF), intrauterine insemination with ovarian stimulation (IUI + SO), clomiphene) at different points in time since diagnosis.WHAT IS KNOWN ALREADYCouples with no identified cause for their subfertility continue to have a realistic chance of conceiving naturally, which makes it difficult for clinicians to decide when to intervene. Previous fertility prediction models have attempted to address this by separately estimating either the chances of natural conception or the chances of conception following certain treatments. These models only make predictions at a single point in time and are therefore inadequate for informing continued decision-making at subsequent consultations.STUDY DESIGN, SIZE, DURATIONA population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011.PARTICIPANTS/MATERIALS, SETTING, METHODSA dynamic prediction model was developed that estimates the chances of conception within 6 months from the point when a diagnosis of unexplained subfertility was made. These predictions were recomputed each month to provide a dynamic assessment of the individualised chances of conception while taking account of treatment status in each month. Conception must have led to live birth and treatments included clomiphene, IUI + SO, and IVF. Predictions for natural conception were externally validated using a prospective cohort from The Netherlands.MAIN RESULTS AND THE ROLE OF CHANCEA total of 554 (42%) couples started fertility treatment within 2 years of their first fertility consultation. The natural conception leading to live birth rate was 0.24 natural conceptions per couple per year. Active treatment had a higher chance of conception compared to those who remained under expectant management. This association ranged from weak with clomiphene to strong with IVF [clomiphene, hazard ratio (HR) = 1.42 (95% confidence interval, 1.05 to 1.91); IUI + SO, HR = 2.90 (2.06 to 4.08); IVF, HR = 5.09 (4.04 to 6.40)]. Female age and duration of subfertility were significant predictors, without clear interaction with the relative effect of treatment.LIMITATIONS, REASONS FOR CAUTIONWe were unable to adjust for other potentially important predictors, e.g. measures of ovarian reserve, which were not available in the linked Grampian dataset that may have made predictions more specific. This study was conducted using single centre data meaning that it may not be generalizable to other centres. However, the model performed as well as previous models in reproductive medicine when externally validated using the Dutch cohort.WIDER IMPLICATIONS OF THE FINDINGSFor the first time, it is possible to estimate the chances of conception following expectant management and different fertility treatments over time in couples with unexplained subfertility. This information will help inform couples and their clinicians of their likely chances of success, which may help manage expectations, not only at diagnostic workup completion but also throughout their fertility journey.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by a Chief Scientist Office postdoctoral training fellowship in health services research and health of the public research (ref PDF/12/06). B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck, and Guerbet. None of the other authors declare any conflicts of interest.
      PubDate: Thu, 23 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez049
      Issue No: Vol. 34, No. 6 (2019)
  • Risk of juvenile idiopathic arthritis among children conceived after
           fertility treatment: a nationwide registry-based cohort study
    • Authors: Sperling C; Kjaer S, Hargreave M, et al.
      Pages: 1139 - 1145
      Abstract: STUDY QUESTIONIs the risk of juvenile idiopathic arthritis (JIA) increased in children conceived after fertility treatment, and is an observed association caused by specific types of fertility treatment or by factors associated with the underlying infertility'SUMMARY ANSWERThe risk of JIA in children conceived after fertility treatment (any and specific types of fertility treatment) was not convincingly affected when compared with children born to fertile women.WHAT IS KNOWN ALREADYIt has been suggested that fertility treatment may affect the development of the immune system and thereby increase the risk of developing autoimmune diseases, including JIA.STUDY DESIGN, SIZE, DURATIONThis retrospective population-based cohort study included all live-born children in Denmark between 1 January 1996 and 31 December 2012 (n = 1 084 184). The study population was followed from date of birth until first diagnosis of JIA as registered in the Danish National Patient Registry, date of 16th birthday, date of emigration, date of death or end of follow-up (31 December 2014), whichever occurred first.PARTICIPANTS/MATERIALS, SETTING, METHODSThe study cohort was linked to the Danish Infertility Cohort in order to identify children born to women with fertility problems (n = 174 702) and fertility treatment (n = 89 931). Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for potential confounders.MAIN RESULTS AND THE ROLE OF CHANCEDuring a median follow-up period of 10.3 years, 2237 children were diagnosed with JIA. Children born to women with fertility problems had an increased risk of JIA (HR 1.18, 95% CI 1.05–1.32) compared with children born to fertile women. However, the risk was not increased in children conceived after any fertility treatment (HR 1.11; 95% CI 0.95–1.29), or after specific types of fertility treatment being ART (HR 1.05; 95% CI 0.83–1.33), IVF (HR 1.01; 95% CI 0.73–1.38), ICSI (HR 0.98; 95% CI 0.64–1.50) or any fertility drugs (HR 1.10; 95% CI 0.94–1.28) compared with children born to fertile women. The associations between fertility treatment and JIA were also assessed by using children born to women with fertility problems without fertility treatment in the index pregnancy as a reference group, however, the findings did not change substantially.LIMITATIONS REASONS FOR CAUTIONDespite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of JIA cases. There may be some misclassification of fertility problems, as some women have undiagnosed fertility problems and are therefore not included in the Danish Infertility Cohort; potentially leading to slight attenuation of the association between fertility problems and JIA.WIDER IMPLICATIONS OF THE FINDINGSThe results are based on national data and our findings can therefore be applied to other similar populations. Our results indicate that fertility treatment per se do not increase the risk of JIA but merely that the increased risk of JIA observed among children born to women with fertility problems may be due to underlying factors related to both infertility and JIA. However, as this is the first large study in this field, further studies are needed to confirm our findings.STUDY FUNDING/COMPETING INTEREST(S)The study was supported by grants from the Jascha Foundation, the Aase and Ejner Danielsens Foundation and The Danish Rheumatism Association. All authors report no conflicts of interest.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Sat, 30 Mar 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez035
      Issue No: Vol. 34, No. 6 (2019)
  • Preimplantation genetic testing for more than one genetic condition:
           clinical and ethical considerations and dilemmas
    • Authors: van der Schoot V; Dondorp W, Dreesen J, et al.
      Pages: 1146 - 1154
      Abstract: STUDY QUESTIONWhich clinical and ethical aspects of preimplantation genetic testing for monogenic disorders or structural rearrangements (PGT-M, PGT-SR) should be considered when accepting requests and counselling couples for PGT when applied for more than one condition (combination-PGT; cPGT-M/SR)'SUMMARY ANSWERcPGT is a feasible extension of the practice of PGT-M/SR that may require adapting the criteria many countries have in place with regard to indications-setting for PGT-M/SR, while leading to complex choices that require timely counselling and information.WHAT IS KNOWN ALREADYAlthough PGT-M/SR is usually performed to prevent transmission of one disorder, requests for PGT-M/SR for more than one condition (cPGT-M/SR) are becoming less exceptional. However, knowledge about implications for a responsible application of such treatments is lacking.STUDY DESIGN, SIZE, DURATIONRetrospective review of all (40) PGT-M/SR applications concerning more than one genetic condition over the period 1995–2018 in the files of the Dutch national PGT centre. This comprises all relevant national data since the start of PGT in the Netherlands.PARTICIPANTS/MATERIALS, SETTING AND METHODSData regarding cPGT-M/SR cases were collected by means of reviewing medical files of couples applying for cPGT-M/SR. Ethical challenges arising with cPGT-M/SR were explored against the background of PGT-M/SR regulations in several European countries, as well as of relevant ESHRE-guidance regarding both indications-setting and transfer-decisions.MAIN RESULTS AND THE ROLE OF CHANCEWe report 40 couples applying for cPGT-M/SR of which 16 couples started their IVF treatment. Together they underwent 39 IVF cycles leading to the birth of five healthy children. Of the couples applying for cPGT, 45% differentiated between a primary and secondary condition in terms of perceived severity. In the light of an altered balance of benefits and drawbacks, we argue the ‘high risk of a serious condition’ standard that many countries uphold as governing indications-setting, should be lowered for secondary conditions in couples who already have an indication for PGT-M/SR. As a consequence of cPGT, professionals will more often be confronted with requests for transferring embryos known to be affected with a condition that they were tested for. In line with ESHRE guidance, such transfers may well be acceptable, on the condition of avoiding a high risk of a child with a seriously diminished quality of life.LIMITATIONS, REASONS FOR CAUTIONWe are the first to give an overview of cPGT-M/SR treatments. Retrospective analysis was performed using national data, possibly not reflecting current trends worldwide.WIDER IMPLICATIONS OF THE FINDINGSOur observations have led to recommendations for cPGT-M/SR that may add to centre policy making and to the formulation of professional guidelines. Given that the introduction of generic methods for genomic analysis in PGT will regularly yield incidental findings leading to transfer requests with these same challenges, the importance of our discussion exceeds the present discussion of cPGT.STUDY FUNDING/COMPETING INTEREST(S)The research for this publication was funded by the Dutch Organization for Health Research and Development (ZonMw), project number: 141111002 (Long term safety, quality and ethics of Preimplantation Genetic Diagnosis). None of the authors has any competing interests to declare.
      PubDate: Thu, 23 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez059
      Issue No: Vol. 34, No. 6 (2019)
  • ADCY10 frameshift variant leading to severe recessive asthenozoospermia
           and segregating with absorptive hypercalciuria
    • Authors: Akbari A; Pipitone G, Anvar Z, et al.
      Pages: 1155 - 1164
      Abstract: STUDY QUESTIONCan whole exome sequencing (WES) reveal a novel pathogenic variant in asthenozoospermia in a multiplex family including multiple patients'SUMMARY ANSWERPatients were discovered to be homozygous for a rare 2-bp deletion in the ADCY10 coding region (c.1205_1206del, rs779944215).WHAT IS KNOWN ALREADYADCY10 encodes for soluble adenylyl cyclase (sAC), which is the predominant adenylate cyclase in sperm. It is already established that proper sAC activity and a constant supply of cAMP are crucial to sperm motility regulation, and knockout mouse models have been reported as severely asthenozoospermic. ADCY10 is a susceptibility gene for dominant absorptive hypercalciuria (OMIM#143870); however, no ADCY10 variations have been confirmed to cause human asthenozoospermia to date.STUDY DESIGN, SIZE, DURATIONThis was a retrospective genetics study of a highly consanguineous pedigree of asthenozoospermia. The subject family was recruited in Iran in 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSThe two patients were diagnosed as asthenozoospermic through careful clinical investigations. Both patients, respective parents, and an unaffected brother were subjected to WES. The discovered variant was validated by Sanger sequencing and segregated with the phenotype. To confirm the pathogenicity of the variant, sperm samples from both patients, 10 normozoospermic men and 10 asthenozoospermic patients not representing the variation, were treated with a cAMP analogue dissolved in human tubal fluid medium, followed by computer-assisted sperm analysis and statistical analyses.MAIN RESULTS AND THE ROLE OF CHANCEThe discovered homozygous variant occurs at 10 amino acids upstream of the ADCY10 nucleotide binding site leading to a premature termination (p.His402Argfs*41). Treatment of the patients’ sperm samples with a cell-permeable cAMP analogue resulted in a significant increase in sperm motility, indicating the pathogenic role of the variant. Moreover, absorptive hypercalciuria, segregating within the family, was also associated with the same variant following a dominant inheritance.LIMITATIONS, REASONS FOR CAUTIONThough nonsense-mediated decay is highly likely to occur in the mutated transcripts, we were not able to confirm this due to low RNA levels in mature sperm.WIDER IMPLICATIONS OF THE FINDINGSOur finding enlarges the phenotypic spectrum associated with the ADCY10 gene, previously described as a susceptibility gene for dominant absorptive hypercalciuria.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by grants from the Royan Institute, Tehran, Iran, and San Raffaele Hospital, Milan, Italy. The authors have no conflict of interest.TRIAL REGISTRATION NUMBERN/A
      PubDate: Thu, 23 May 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez048
      Issue No: Vol. 34, No. 6 (2019)
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