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Relationship Between Sperm Head Vacuoles and Sperm DNA Alterations in Infertile Men (VATES)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02006446
First Posted: December 10, 2013
Last Update Posted: January 20, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
University Hospital, Rouen
  Purpose

In men presenting sperm alterations, the selection of genetically undamaged spermatozoa need to be improved in order to increase the success of assisted reproduction treatments.

The aim of this study is to determine whether the presence of sperm head vacuoles is associated with sperm DNA alterations.


Condition
Male Infertility

Study Type: Observational [Patient Registry]
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 1 Day
Official Title: Are Sperm Head Vacuoles Associated With Sperm Nuclear Alterations?

Resource links provided by NLM:


Further study details as provided by University Hospital, Rouen:

Primary Outcome Measures:
  • Correlation coefficient between mean vacuole areas in sperm heads (measured by MSOME) and sperm aneuploidy rates for chromosomes X, Y and 18 (evaluated by FISH) [ Time Frame: up to 30 months ]

Secondary Outcome Measures:
  • Total sperm count [ Time Frame: 1 day ]
  • Percentage of mobile spermatozoa [ Time Frame: 1 day ]
  • Percentage of morphologically abnormal spermatozoa [ Time Frame: 1 day ]
  • Mean vacuole area threshold (measured with Receiver Operating Characteristic curves) [ Time Frame: up to 30 months ]
  • Correlation coefficient between vacuole areas and sperm DNA fragmentation (evaluated by TUNEL analysis) [ Time Frame: up to 30 months ]
  • Correlation coefficient between vacuole areas and abnormal chromatin condensation (evaluated by aniline blue staining) [ Time Frame: up to 30 months ]
  • Correlation coefficient between vacuole areas and telomere number, distribution and length (evaluated by quantitative FISH) [ Time Frame: up to 30 months ]

Biospecimen Retention:   Samples Without DNA
spermatozoa

Enrollment: 200
Actual Study Start Date: December 2013
Study Completion Date: January 2017
Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Groups/Cohorts
VATES
men with altered spermograms (isolated teratozoospermia or oligo-astheno-teratozoospermia)

Detailed Description:

The use of intracytoplasmic sperm injection (ICSI) has greatly improved the treatment of severe male infertility, especially for men with oligo-astheno-teratozoospermia (OAT). This in vitro fertilization procedure allows the direct injection of a single spermatozoon into an oocyte. The sperm used for ICSI is selected under a microscope at a 400x magnification. Several studies have reported that de novo chromosomal abnormalities are increased in children born from ICSI , thereby raising the question of the genetic quality of spermatozoa used for ICSI.

A method called MSOME (high magnification Motile Sperm Organelle Morphology Examination), which allows the detailed morphological evaluation of motile spermatozoa in real time and under high magnification (6600x), was developed in 2001. With this technique, fine morphological abnormalities - mainly vacuoles in the head of spermatozoa - were detected. The use of MSOME for the detection of morphologically normal sperm for ICSI gave rise to a technique called IMSI (Intracytoplasmic Morphologically Selected sperm Injection). Higher pregnancy rates were obtained with IMSI compared to ICSI and sperm head vacuoles were found to negatively affect assisted reproduction success rates and embryo development. The use of IMSI also decreases the risk of sex chromosome aneuploidy in embryos .

Several authors found that the presence of large vacuoles in the sperm head correlates with several nuclear alterations: DNA fragmentation , abnormal chromatin condensation and aneuploidy . However, these studies are controversial and were performed on few spermatozoa. In order to improve the selection of spermatozoa with a normal chromosomal content, it is essential not only to confirm the existence of a relationship between sperm head vacuoles and altered sperm nuclear quality but also to better characterize these alterations.

The main goal of this study is to investigate the correlation between sperm head vacuole areas and sperm aneuploidy rates in men with isolated teratozoospermia or OAT. Vacuole areas will be measured by MSOME and aneuploidy rates by FISH for chromosomes 18, X and Y. Moreover, the correlation between sperm head vacuole areas and other nuclear alterations (DNA fragmentation, abnormal chromatin condensation, telomere abnormalities) will be evaluated. Semen samples from 200 patients recruited over a 2-year period will be collected, stored and analyzed.

This study involves the collection of relevant medical information. The computer website for the patient database is secure and protected by a password. The information will be entered and only be viewed by the investigators. On-site monitoring visits will be conducted throughout the study.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
infertile men attending the assisted reproduction units in Rouen and Lille
Criteria

Inclusion Criteria:

  • men
  • 18 years old or more
  • affiliated to social security
  • with isolated teratozoospermia or oligo-astheno-teratozoospermia according to the WHO guidelines (2010):

    • sperm concentration < 15 million per ml or sperm number < 39 million per ejaculate
    • progressive motility < 35%
    • morphologically normal forms < 50% according to the modified David's classification (Auger et al., 2001
    • mobile spermatozoa selected by density gradient centrifugation > 1 million, in previous spermograms
  • with normal constitutional karyotypes (46, XY)
  • signed an informed consent

Exclusion Criteria:

  • with abnormal constitutional karyotypes
  • with a major alteration of sperm parameters, with mobile spermatozoa selected by density gradient centrifugation < 1 million
  • under tutorship or guardianship by court order
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02006446


Locations
France
Laboratoire de spermiologie, CHRU de Lille
Hôpital Calmette CHRU de Lille, France
Laboratoire de Biologie de la Reproduction - CECOS - EA 4308, CHU - Hôpitaux de Rouen
Rouen, France, 76031
Sponsors and Collaborators
University Hospital, Rouen
Investigators
Principal Investigator: Nathalie Rives, MD., PhD. Laboratoire de Biologie de la Reproduction - CECOS - EA 4308, CHU - Hôpitaux de Rouen
  More Information

Publications:
Antinori M, Licata E, Dani G, Cerusico F, Versaci C, d'Angelo D, Antinori S. Intracytoplasmic morphologically selected sperm injection: a prospective randomized trial. Reprod Biomed Online. 2008 Jun;16(6):835-41.
Auger J, Eustache F, Andersen AG, Irvine DS, Jørgensen N, Skakkebaek NE, Suominen J, Toppari J, Vierula M, Jouannet P. Sperm morphological defects related to environment, lifestyle and medical history of 1001 male partners of pregnant women from four European cities. Hum Reprod. 2001 Dec;16(12):2710-7.
Bartoov B, Berkovitz A, Eltes F. Selection of spermatozoa with normal nuclei to improve the pregnancy rate with intracytoplasmic sperm injection. N Engl J Med. 2001 Oct 4;345(14):1067-8.
Bartoov B, Berkovitz A, Eltes F, Kogosovsky A, Yagoda A, Lederman H, Artzi S, Gross M, Barak Y. Pregnancy rates are higher with intracytoplasmic morphologically selected sperm injection than with conventional intracytoplasmic injection. Fertil Steril. 2003 Dec;80(6):1413-9.
Boitrelle F, Ferfouri F, Petit JM, Segretain D, Tourain C, Bergere M, Bailly M, Vialard F, Albert M, Selva J. Large human sperm vacuoles observed in motile spermatozoa under high magnification: nuclear thumbprints linked to failure of chromatin condensation. Hum Reprod. 2011 Jul;26(7):1650-8. doi: 10.1093/humrep/der129. Epub 2011 May 2.
Bonduelle M, Van Assche E, Joris H, Keymolen K, Devroey P, Van Steirteghem A, Liebaers I. Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod. 2002 Oct;17(10):2600-14.
Figueira Rde C, Braga DP, Setti AS, Iaconelli A Jr, Borges E Jr. Morphological nuclear integrity of sperm cells is associated with preimplantation genetic aneuploidy screening cycle outcomes. Fertil Steril. 2011 Mar 1;95(3):990-3. doi: 10.1016/j.fertnstert.2010.11.018. Epub 2010 Dec 4.
Foresta C, Garolla A, Bartoloni L, Bettella A, Ferlin A. Genetic abnormalities among severely oligospermic men who are candidates for intracytoplasmic sperm injection. J Clin Endocrinol Metab. 2005 Jan;90(1):152-6. Epub 2004 Oct 27.
Franco JG Jr, Baruffi RL, Mauri AL, Petersen CG, Oliveira JB, Vagnini L. Significance of large nuclear vacuoles in human spermatozoa: implications for ICSI. Reprod Biomed Online. 2008 Jul;17(1):42-5.
Franco JG Jr, Mauri AL, Petersen CG, Massaro FC, Silva LF, Felipe V, Cavagna M, Pontes A, Baruffi RL, Oliveira JB, Vagnini LD. Large nuclear vacuoles are indicative of abnormal chromatin packaging in human spermatozoa. Int J Androl. 2012 Feb;35(1):46-51. doi: 10.1111/j.1365-2605.2011.01154.x. Epub 2011 Apr 28.
Garolla A, Fortini D, Menegazzo M, De Toni L, Nicoletti V, Moretti A, Selice R, Engl B, Foresta C. High-power microscopy for selecting spermatozoa for ICSI by physiological status. Reprod Biomed Online. 2008 Nov;17(5):610-6.
Hazout A, Dumont-Hassan M, Junca AM, Cohen Bacrie P, Tesarik J. High-magnification ICSI overcomes paternal effect resistant to conventional ICSI. Reprod Biomed Online. 2006 Jan;12(1):19-25.
Oliveira JB, Massaro FC, Baruffi RL, Mauri AL, Petersen CG, Silva LF, Vagnini LD, Franco JG Jr. Correlation between semen analysis by motile sperm organelle morphology examination and sperm DNA damage. Fertil Steril. 2010 Oct;94(5):1937-40. doi: 10.1016/j.fertnstert.2010.01.042. Epub 2010 Mar 2.
Perdrix A, Travers A, Chelli MH, Escalier D, Do Rego JL, Milazzo JP, Mousset-Siméon N, Macé B, Rives N. Assessment of acrosome and nuclear abnormalities in human spermatozoa with large vacuoles. Hum Reprod. 2011 Jan;26(1):47-58. doi: 10.1093/humrep/deq297. Epub 2010 Nov 18.
Van Steirteghem A, Bonduelle M, Devroey P, Liebaers I. Follow-up of children born after ICSI. Hum Reprod Update. 2002 Mar-Apr;8(2):111-6. Review.
Vanderzwalmen P, Hiemer A, Rubner P, Bach M, Neyer A, Stecher A, Uher P, Zintz M, Lejeune B, Vanderzwalmen S, Cassuto G, Zech NH. Blastocyst development after sperm selection at high magnification is associated with size and number of nuclear vacuoles. Reprod Biomed Online. 2008 Nov;17(5):617-27.
Watanabe S, Tanaka A, Fujii S, Mizunuma H, Fukui A, Fukuhara R, Nakamura R, Yamada K, Tanaka I, Awata S, Nagayoshi M. An investigation of the potential effect of vacuoles in human sperm on DNA damage using a chromosome assay and the TUNEL assay. Hum Reprod. 2011 May;26(5):978-86. doi: 10.1093/humrep/der047. Epub 2011 Feb 28.
Wilding M, Coppola G, di Matteo L, Palagiano A, Fusco E, Dale B. Intracytoplasmic injection of morphologically selected spermatozoa (IMSI) improves outcome after assisted reproduction by deselecting physiologically poor quality spermatozoa. J Assist Reprod Genet. 2011 Mar;28(3):253-62. doi: 10.1007/s10815-010-9505-5. Epub 2010 Nov 12.

Responsible Party: University Hospital, Rouen
ClinicalTrials.gov Identifier: NCT02006446     History of Changes
Other Study ID Numbers: 2013/005/HP
First Submitted: November 25, 2013
First Posted: December 10, 2013
Last Update Posted: January 20, 2017
Last Verified: January 2017

Keywords provided by University Hospital, Rouen:
Male infertility
sperm head vacuoles
sperm morphology
aneuploidy
DNA fragmentation
abnormal chromatin condensation
telomere abnormalities

Additional relevant MeSH terms:
Infertility
Infertility, Male
Genital Diseases, Male
Genital Diseases, Female


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