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

Male Sterility Due to Y-chromosome Deletions Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02527954
• Other study ID #: 1412-ALC-086-PH
• Status: Terminated
• Start date: September 22, 2015
• Est. completion date: June 11, 2018

Study information

• Verified date: March 2019
• Source: Instituto Valenciano de Infertilidad, IVI Alicante
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: June 11, 2018
• Est. primary completion date: June 11, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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.

Related Conditions & MeSH terms

• Aneuploidy
• Chromosome Deletion
• Infertility
• Infertility, Male
• Male Sterility Due to Y-chromosome Deletions
• Sex Chromosome Aberrations

Locations

Country	Name	City	State
Spain	IVI Alicante	Alicante
Spain	IVI Murcia	Murcia
Spain	Igenomix	Valencia

Sponsors (3)

Lead Sponsor	Collaborator
Instituto Valenciano de Infertilidad, IVI Alicante	Igenomix, IVI Murcia

Country where clinical trial is conducted

Spain, 

References & Publications (27)

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Mulhall JP, Reijo R, Alagappan R, Brown L, Page D, Carson R, Oates RD. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod. 1997 Mar;12(3):503-8. — View Citation

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Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I. The choice and outcome of the fertility treatment of 38 couples in whom the male partner has a Yq microdeletion. Hum Reprod. 2005 Jul;20(7):1887-96. Epub 2005 Mar 24. — View Citation

Suganthi R, Vijesh VV, Vandana N, Fathima Ali Benazir J. Y choromosomal microdeletion screening in the workup of male infertility and its current status in India. Int J Fertil Steril. 2014 Jan;7(4):253-66. Epub 2013 Dec 22. Review. — View Citation

van Golde RJ, Wetzels AM, de Graaf R, Tuerlings JH, Braat DD, Kremer JA. Decreased fertilization rate and embryo quality after ICSI in oligozoospermic men with microdeletions in the azoospermia factor c region of the Y chromosome. Hum Reprod. 2001 Feb;16(2):289-92. — View Citation

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* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	% Embryos with aneuploidies	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	% Spermatozoa with aneuploidies	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
Secondary	Fertilization rate (%)	nº fertilized oocytes/ nº metaphase II oocytes	three years
Secondary	Day 3 embryos rate (%)	nº embryos at day 3/ nº fertilized oocytes	Three years
Secondary	Blastocyst rate (%)	nº blastocyst/ nº fertilized oocytes	Three years
Secondary	Cycle efficiency	nº transferred embryos + vitrified embryos	Four years
Secondary	Pregnancy rate (%)	nº pregnancies/ nº embryos transferred	Four years
Secondary	Biochemical pregnancy rate (%)	% of positive pregnancy tests	Four years
Secondary	Clinical pregnancy rate (%)	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
Secondary	Implantation rate (%)	nº gestational sacs/ nº transferred embryos	Four years
Secondary	Abortion rate (%)	nº miscarriages/ nº pregnancies.	Four years
Secondary	Ongoing pregnancy rate (%)	% clinical pregnancies that do not finish in abortion or ectopic pregnancy	Four years
Secondary	Live birth rate (%)	Proportion of live birth at home per embryo transferred.	Four years