Aneuploidies in Embryos and Spermatozoa From Patients With Y-chromosome Microdeletions

March 6, 2019 updated by: Purificación Hernández, Instituto Valenciano de Infertilidad, IVI Alicante

Impact of Y-chromosome Microdeletions From Infertile Men on the Chromosomal Constitution of Their Spermatozoa and Embryos. Combined IntraCytoplasmatic Sperm Injection (ICSI) and Preimplantation Genetic Screening (PGS) as Treatment Strategy.

In this study, investigators assess, using Fluorescence in situ Hybridization (FISH) and Comparative Genomic Hybridization (CGH) arrays for Preimplantation Genetic Screening (PGS), the incidence of aneuploidies in spermatozoa and embryos from infertile men with and without microdeletions who undergo assisted reproduction in their clinics.

Study Overview

Status

Terminated

Conditions

Detailed Description

Nowadays, Y-chromosome microdeletions are one of the most common causes of male infertility. With a frequency of 8-20% in non-obstructive azoospermic men and 3-14% in severe oligozoospermic men, is the most usual chromosome anomaly associated with failure in sperm production, although the frequency seems to change due to differences in the experimental designs, the ethnic differences, the genetic background, or even environmental influences.

The absence of some genes located on certain regions in the long arm of the human Y chromosome, known as the azoospermia factor region (AZF), causes spermatogenic failure, while spermatozoa has been found in either the ejaculate or the testicle of most patients. Detection of deletions is crucial for the medical treatment of these patients, since it has a prognostic value in predicting potential success of testicular sperm retrieval in azoospermic patients with certain microdeletions, and allows avoiding invasive techniques in oligozoospermic patients whose sperm production could result in progressive worsening.

The development of assisted reproduction techniques, such as intracytoplasmatic sperm injection (ICSI), together with testicular or epididymis sperm retrieval for azoospermic men has allowed these patients to become fathers using their own gametes. Although the effect of Y-chromosome microdeletions on ICSI outcome is controversial, the ability to vertically transmit that genetic defect, and so the infertility, to the offspring has been accepted. Until recently, no clinical consequences other than infertility were supposed in the ICSI-conceived sons of fathers with deletions. However, different studies in the last years, suggest other potentially risks transmitted to the offspring, such as the development of sexual dysfunction due to sex chromosome abnormalities (Turner or Klinefelter syndromes, etc.) or other somatic disorders with worse health implications caused by chromosome aberrations outside the AZF regions or in autosomes that has been associated to Y-chromosome microdeletions. No major clinical complications than infertility has been described in the offspring born from fathers with deletions to date, but it is important to remember that the first generation of those babies, mainly obtained by ICSI, has just reached maturity. Moreover, the mentioned chromosome anomalies, could stop embryo development or increase miscarriage rate. Few studies focused in the incidence of miscarriages in these couples but microdeletions have been detected more frequents in men from couples with recurrent pregnancy loss.

In order to offer fully genetic counseling to these couples, further studies focusing on the relationship between Y-chromosome microdeletions and other chromosomal abnormalities, which also provide information about their consequences in their embryos, are required. Thus, the actual risk of transmitting different anomalies associated to microdeletions to those embryos will be clarified, increasing the chances of a successful pregnancy and live birth.

In this study, investigators assess, using Fluorescence in situ Hybridization (FISH) and Comparative Genomic Hybridization (CGH) arrays for Preimplantation Genetic Screening (PGS), the incidence of aneuploidies in spermatozoa and embryos from infertile men with and without microdeletions who undergo assisted reproduction in their clinics.

Study Type

Observational

Enrollment (Actual)

5

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Alicante, Spain, 03015
        • IVI Alicante
      • Murcia, Spain, 03007
        • IVI Murcia
      • Valencia, Spain, 41980
        • Igenomix

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 50 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Couples undergoing "In vitro" Fertilization (IVF) treatment whose man has non-obstructive azoospermia or severe oligozoospermia (≤ 5x1000000 spermatozoa/ml) and consent the genetic analysis of semen samples, as well as the embryo cohort generated by ICSI.

Description

Inclusion Criteria:

  1. Couples with male infertility whose man has non-obstructive azoospermia or severe oligozoospermia with ≤5x1000000 spermatozoa/ml.
  2. Assisted Reproductive Technology: ICSI with motile spermatozoa and PGS by CGH arrays.
  3. Women <38 years if microinjection is carried out in their own eggs, or 38≤ age <50 years if they receive donated eggs.
  4. Women with body mass index (BMI)<30.
  5. Men<50 years

Exclusion Criteria:

  1. Couples with abnormal karyotypes.
  2. Women with any uterine pathology or abnormality, hydrosalpinx, thrombophilia or systemic diseases at the time of embryo transfer that could prejudge the outcome of the cycle
  3. Couples with repeated miscarriages (≥2) or implantation failures (≥2).
  4. Couples whose men has obstructive azoospermia, genital tract infections (mumps, inflammation, varicocele), cryptorchidism, or if he receives any treatment that can reduce the sperm count.
  5. Seminal samples processed by Magnetic Activated Cell Sorting (MACS) technique.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Infertile with Y-chromosome deletions

No intervention will be performed.

Couples whose infertile men has a Y-chromosome microdeletion (detected in blood cells by Polymerase chain reaction multiplex) and fulfill the criteria will be included in this group (group 1)
Infertile without Y-chromosome deletions

No intervention will be performed.

Couples whose infertile men has not any Y-chromosome microdeletion (detected in blood cells by polymerase chain reaction multiplex) and fulfill the criteria will be included in this group (group 2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
% Embryos with aneuploidies
Time Frame: three years

The incidence of embryonic aneuploidies will be examined by CGH arrays analysis after biopsy in day 3 or day 5 of embryo development. This technology allows the analysis of all the chromosomes, so both aneuploidies in gonosomes and autosomes will be determined.

To measure these percentages the images obtained after CGH array will be analyzed by BlueFuse Software (BlueGnome, Cambridge, UK), identifying normal euploid embryos, embryos with full or partial aneuploidy and chaotic embryos.
three years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
% Spermatozoa with aneuploidies
Time Frame: Three years

The incidence of aneuploidy (%) in sperm will be examined by FISH, analyzing chromosomes 13, 18, 21, X and Y.

To measure these percentages two examiners will analyze 2000 spermatozoa in each sample.
Three years
Fertilization rate (%)
Time Frame: three years
nº fertilized oocytes/ nº metaphase II oocytes
three years
Day 3 embryos rate (%)
Time Frame: Three years
nº embryos at day 3/ nº fertilized oocytes
Three years
Blastocyst rate (%)
Time Frame: Three years
nº blastocyst/ nº fertilized oocytes
Three years
Cycle efficiency
Time Frame: Four years
nº transferred embryos + vitrified embryos
Four years
Pregnancy rate (%)
Time Frame: Four years
nº pregnancies/ nº embryos transferred
Four years
Biochemical pregnancy rate (%)
Time Frame: Four years
% of positive pregnancy tests
Four years
Clinical pregnancy rate (%)
Time Frame: Four years
nº pregnancies (proven by the presence of at least 1 embryo with cardiac activity positive by ultrasound after 5-6 weeks of development)/ nº of transfer cycles
Four years
Implantation rate (%)
Time Frame: Four years
nº gestational sacs/ nº transferred embryos
Four years
Abortion rate (%)
Time Frame: Four years
nº miscarriages/ nº pregnancies.
Four years
Ongoing pregnancy rate (%)
Time Frame: Four years
% clinical pregnancies that do not finish in abortion or ectopic pregnancy
Four years
Live birth rate (%)
Time Frame: Four years
Proportion of live birth at home per embryo transferred.
Four years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Instituto Valenciano de Infertilidad, IVI Alicante

Collaborators

Igenomix
IVI Murcia

Investigators

  • Principal Investigator: Purificación Hernández-Vargas, PhD, Instituto Valenciano de Infertilidad, IVI Alicante

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 22, 2015

Primary Completion (Actual)

June 11, 2018

Study Completion (Actual)

June 11, 2018

Study Registration Dates

First Submitted

August 11, 2015

First Submitted That Met QC Criteria

August 17, 2015

First Posted (Estimate)

August 19, 2015

Study Record Updates

Last Update Posted (Actual)

March 8, 2019

Last Update Submitted That Met QC Criteria

March 6, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1412-ALC-086-PH

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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