Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome

Study Overview
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Brief Summary
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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
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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.

Official Title
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Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome

Conditions
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Fertility Preservation, Ovarian Tissue Cryopreservation, Turner Syndrome, Live Birth, Premature Ovarian Failure

Intervention / Treatment
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* Procedure: Ovarian tissue cryopreservation


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single cohort<br> | Procedure: Ovarian tissue cryopreservation<br>* Laparoscopic unilateral oophorectomy followed by cryopreservation of ovarian cortex tissue<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth ratio (LBR) (main outcome) | • Live birth after auto transplantation of cryopreserved-thawed ovarian cortical tissue (i.e. live birth rate or LBR) | Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation. | 
| Number of primordial follicles (proximate) | The number of primordial follicles found in the ovarian tissue | Within 1 month after ovarian tissue cryopreservation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient's age versus LBR | The association between patient's age at cryopreservation and LBR | Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation. | 
| Patient's genotype versus LBR | The association between patient's genotype and LBR | Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation. | 
| Patient's Anti-Müllerian hormone (AMH) level versus LBR | The association between patient's AMH level at cryopreservation and LBR | Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation. | 
| Patient's Follicle-stimulating hormone (FSH) level versus LBR | The association between patient's FSH level at cryopreservation and LBR | Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation. |