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Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome

Primary Purpose

Fertility Preservation, Ovarian Tissue Cryopreservation, Turner Syndrome

Status
Active
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Ovarian tissue cryopreservation
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fertility Preservation

Eligibility Criteria

2 Years - 18 Years (Child, Adult)FemaleDoes not accept healthy volunteers

Inclusion criteria

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

  • Girls and young females with classic Turner (i.e. 45X monosomy) or Turner variants (e.g. 45X / 46XX mosaicism, ring X mosaicism, isochromosome X),
  • Aged 2 through 18 years,
  • who completed the diagnostic work up phase of TS including routine cardiac screening*,
  • whose agreement to participate in this study has been signed by the parents (girls 2-11 years old),
  • whose agreement to participate in this study has been signed by the patient and her parents (girls 12-17 years old),
  • whose agreement to participate in this study has been signed by the patient (adolescents of 18 years old).

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

  • Contra-indications for laparoscopic unilateral oophorectomy under general anaesthesia (e.g. severe cardiovascular comorbidity and/or BMI >40 kg/m2)*,

  • Contra-indications for cryopreservation (i.e. active HIV, hepatitis-B or hepatitis-C infection)

    • Based on the international Cincinnati Turner Guideline consensus Meeting, July 2016 and consultation of Dutch cardiologists, paediatric-cardiologists and anaesthesists between 2016-2017 there are no absolute cardiovascular contra-indications for surgical intervention and/or pregnancy. Advice against surgical intervention and/or pregnancy should be based on the patient-specific cardiovascular risk profile. The 2% mortality risk due to acute aortic dissection is based on one survey and literature review study that reported the outcomes of 101 pregnancies in patients with TS after oocyte donation. Only 50% of the patients were screened by a cardiologist before entering the oocyte donation programme. Therefore, all girls who want to participate in this study should have completed the diagnostic work up phase of TS including routine cardiac screening and will be screened by a paediatric anaesthesist. Exclusion will be based on the patient specific risk profile. See: References.

Sites / Locations

  • Radboud university medical center. Department Obstetrics & Gynaecology.

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Single cohort

Arm Description

Outcomes

Primary Outcome Measures

Live birth ratio (LBR) (main outcome)
• Live birth after auto transplantation of cryopreserved-thawed ovarian cortical tissue (i.e. live birth rate or LBR)
Number of primordial follicles (proximate)
The number of primordial follicles found in the ovarian tissue

Secondary Outcome Measures

Patient's age versus LBR
The association between patient's age at cryopreservation and LBR
Patient's genotype versus LBR
The association between patient's genotype and LBR
Patient's Anti-Müllerian hormone (AMH) level versus LBR
The association between patient's AMH level at cryopreservation and LBR
Patient's Follicle-stimulating hormone (FSH) level versus LBR
The association between patient's FSH level at cryopreservation and LBR

Full Information

First Posted
November 22, 2017
Last Updated
April 27, 2022
Sponsor
Radboud University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03381300
Brief Title
Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome
Official Title
Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 1, 2018 (Actual)
Primary Completion Date
December 31, 2022 (Anticipated)
Study Completion Date
November 1, 2071 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Rationale: Infertility due is a major concern for girls with Turner syndrome (TS) and their parents. Physicians are often asked about possible options to preserve their fertility. However, despite some experimental case reports, clear evidence for fertility preservation in these girls is lacking and many questions remain. Without evidence on the effectiveness of fertility preservation it cannot routinely be offered to girls with TS. Objective: To investigate the occurrence of live birth in women with TS after ovarian tissue cryopreservation in childhood followed by auto transplantation in adulthood. Study design: A national multicentre exploratory intervention study Study population: Girls diagnosed with Turner Syndrome, aged 2-18 years. Intervention: Ovarian tissue cryopreservation in childhood followed by auto transplantation in adulthood. In order to obtain the ovarian tissue for cryopreservation, all girls must undergo a laparoscopy under general anaesthesia which will be performed in academic/university clinics with paediatric surgery. During the laparoscopic intervention, a unilateral oophorectomy will be performed, thereby leaving the other ovary intact for hormone production, ovulation, spontaneous pregnancies and as an auto transplantation site for cryopreserved-thawed ovarian cortical tissue later on. Furthermore, a small sample of the ovarian cortex will be used to assess the oocyte quality and genetics (e.g. the presence of germ line mosaicism). Oocytes will be karyotyped by using Fluorescence in situ hybridization (FISH). Karyotypic and hormonal data will be collected once at the yearly clinical visit at the paediatric-endocrinologist. Therefore, a buccal swab and one extra blood sample will be taken and evaluated during the routine laboratory evaluation. In the future, auto transplantation of frozen-thawed ovarian cortex strips will be performed.
Detailed Description
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The primary objective remains to preserve the fertility of the respective (minor) patient, facing a very high risk of premature ovarian insufficiency (POI) of 95-98%. Disadvantages of participating in this study are the potential risk of complications related to the laparoscopic unilateral oophorectomy and/or the unknown effect on future fertility of these girls. Moreover, the procedure might raise false hope in patients (and/or parents) about the chance of getting pregnant after auto transplantation of cryopreserved-thawed ovarian tissue in the future. However, we attempt to overcome this by extensive and objective information provision by both written materials and face to face counselling.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fertility Preservation, Ovarian Tissue Cryopreservation, Turner Syndrome, Live Birth, Premature Ovarian Failure

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
106 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Single cohort
Arm Type
Other
Intervention Type
Procedure
Intervention Name(s)
Ovarian tissue cryopreservation
Intervention Description
Laparoscopic unilateral oophorectomy followed by cryopreservation of ovarian cortex tissue
Primary Outcome Measure Information:
Title
Live birth ratio (LBR) (main outcome)
Description
• Live birth after auto transplantation of cryopreserved-thawed ovarian cortical tissue (i.e. live birth rate or LBR)
Time Frame
Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
Title
Number of primordial follicles (proximate)
Description
The number of primordial follicles found in the ovarian tissue
Time Frame
Within 1 month after ovarian tissue cryopreservation
Secondary Outcome Measure Information:
Title
Patient's age versus LBR
Description
The association between patient's age at cryopreservation and LBR
Time Frame
Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
Title
Patient's genotype versus LBR
Description
The association between patient's genotype and LBR
Time Frame
Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
Title
Patient's Anti-Müllerian hormone (AMH) level versus LBR
Description
The association between patient's AMH level at cryopreservation and LBR
Time Frame
Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
Title
Patient's Follicle-stimulating hormone (FSH) level versus LBR
Description
The association between patient's FSH level at cryopreservation and LBR
Time Frame
Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
Other Pre-specified Outcome Measures:
Title
Study participation rate
Description
The willingness of girls with TS to perform a unilateral oophorectomy for fertility preservation (i.e. the study participation rate)
Time Frame
Up to 3 years after inclusion
Title
Eligible participants
Description
The number of eligible participants
Time Frame
Up to 3 years after inclusion
Title
Age
Description
The age of the participant
Time Frame
Up to 3 years after inclusion
Title
Buccal cells versus peripheral lymphocytes
Description
The incidence of somatic mosaicism (i.e. buccal cells versus peripheral lymphocytes)
Time Frame
Up to 3 years after inclusion
Title
Ovarian cells versus peripheral lymphocytes
Description
The incidence of germ cell mosaicism (i.e. ovarian cells versus peripheral lymphocytes and buccal cells)
Time Frame
Up to 3 years after inclusion
Title
Serum hormone levels
Description
Serum hormone levels (i.e. FSH, Luteinizing hormone (LH), AMH, E2, inhibin B)
Time Frame
Up to 3 years after inclusion
Title
Complication rate
Description
The number of complications related to the laparoscopic procedure
Time Frame
Up to 1 year after the laparoscopic procedure
Title
Influence of laparoscopic oophorectomy on puberty and/or menarche
Description
The incidence of puberty and/or menarche after laparoscopic oophorectomy
Time Frame
Up to 10 years after the laparoscopic procedure
Title
Incidence of spontaneous pregnancies
Description
The incidence of spontaneous pregnancies after laparoscopic oophorectomy
Time Frame
Up to 45 years after the laparoscopic procedure
Title
Restoration of ovarian function after auto transplantation of ovarian tissue
Description
The incidence of menstruation cycle recovery after auto transplantation of cryopreserved-thawed ovarian tissue in the future
Time Frame
Up to 2 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Title
Pregnancies after auto transplantation of ovarian tissue
Description
The incidence of pregnancies after auto transplantation of cryopreserved-thawed ovarian tissue in the future
Time Frame
Up to 2 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Title
Ongoing pregnancies after auto transplantation of ovarian tissue
Description
The incidence of ongoing pregnancies after auto transplantation of cryopreserved-thawed ovarian tissue in the future
Time Frame
Up to 2 years and 3 months after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Title
Miscarriages after auto transplantation of ovarian tissue
Description
The number of miscarriages after auto transplantation of cryopreserved-thawed ovarian tissue in the future
Time Frame
Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Title
Time to pregnancy after auto transplantation of ovarian tissue
Description
Time to pregnancy after auto transplantation of cryopreserved-thawed ovarian tissue in the future
Time Frame
Up to 2 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Title
Time to live birth after auto transplantation of ovarian tissue
Description
Time to live birth after auto transplantation of cryopreserved-thawed ovarian tissue in the future
Time Frame
Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Patients 45X monosomy of mosaicism
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria In order to be eligible to participate in this study, a subject must meet all of the following criteria: Girls and young females with classic Turner (i.e. 45X monosomy) or Turner variants (e.g. 45X / 46XX mosaicism, ring X mosaicism, isochromosome X), Aged 2 through 18 years, who completed the diagnostic work up phase of TS including routine cardiac screening*, whose agreement to participate in this study has been signed by the parents (girls 2-11 years old), whose agreement to participate in this study has been signed by the patient and her parents (girls 12-17 years old), whose agreement to participate in this study has been signed by the patient (adolescents of 18 years old). Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: Contra-indications for laparoscopic unilateral oophorectomy under general anaesthesia (e.g. severe cardiovascular comorbidity and/or BMI >40 kg/m2)*, Contra-indications for cryopreservation (i.e. active HIV, hepatitis-B or hepatitis-C infection) Based on the international Cincinnati Turner Guideline consensus Meeting, July 2016 and consultation of Dutch cardiologists, paediatric-cardiologists and anaesthesists between 2016-2017 there are no absolute cardiovascular contra-indications for surgical intervention and/or pregnancy. Advice against surgical intervention and/or pregnancy should be based on the patient-specific cardiovascular risk profile. The 2% mortality risk due to acute aortic dissection is based on one survey and literature review study that reported the outcomes of 101 pregnancies in patients with TS after oocyte donation. Only 50% of the patients were screened by a cardiologist before entering the oocyte donation programme. Therefore, all girls who want to participate in this study should have completed the diagnostic work up phase of TS including routine cardiac screening and will be screened by a paediatric anaesthesist. Exclusion will be based on the patient specific risk profile. See: References.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kathrin Fleischer, MD, PhD
Organizational Affiliation
Head Department of Reproductive Medicine, Gynaecologist/Subspecialist Reproductive Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Radboud university medical center. Department Obstetrics & Gynaecology.
City
Nijmegen
State/Province
Gelderland
ZIP/Postal Code
6500HB
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
28705803
Citation
Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, Lin AE, Mauras N, Quigley CA, Rubin K, Sandberg DE, Sas TCJ, Silberbach M, Soderstrom-Anttila V, Stochholm K, van Alfen-van derVelden JA, Woelfle J, Backeljauw PF; International Turner Syndrome Consensus Group. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017 Sep;177(3):G1-G70. doi: 10.1530/EJE-17-0430.
Results Reference
background
PubMed Identifier
33342535
Citation
Nadesapillai S, van der Velden J, Smeets D, van de Zande G, Braat D, Fleischer K, Peek R. Why are some patients with 45,X Turner syndrome fertile? A young girl with classical 45,X Turner syndrome and a cryptic mosaicism in the ovary. Fertil Steril. 2021 May;115(5):1280-1287. doi: 10.1016/j.fertnstert.2020.11.006. Epub 2020 Dec 17.
Results Reference
derived
PubMed Identifier
31831533
Citation
Schleedoorn M, van der Velden J, Braat D, Beerendonk I, van Golde R, Peek R, Fleischer K. TurnerFertility trial: PROTOCOL for an observational cohort study to describe the efficacy of ovarian tissue cryopreservation for fertility preservation in females with Turner syndrome. BMJ Open. 2019 Dec 11;9(12):e030855. doi: 10.1136/bmjopen-2019-030855.
Results Reference
derived
PubMed Identifier
31398245
Citation
Peek R, Schleedoorn M, Smeets D, van de Zande G, Groenman F, Braat D, van der Velden J, Fleischer K. Ovarian follicles of young patients with Turner's syndrome contain normal oocytes but monosomic 45,X granulosa cells. Hum Reprod. 2019 Sep 29;34(9):1686-1696. doi: 10.1093/humrep/dez135.
Results Reference
derived

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Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome

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