Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome

Turner Syndrome Clinical Trial

Official title:

Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03381300
• Other study ID #: NL57738.000.16
• Status: Active, not recruiting
• Phase: N/A
• Start date: January 1, 2018
• Est. completion date: November 1, 2071

Study information

• Verified date: May 2021
• Source: Radboud University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 106
• Est. completion date: November 1, 2071
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 2 Years to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fertility Preservation
• Gonadal Dysgenesis
• Live Birth
• Menopause, Premature
• Ovarian Tissue Cryopreservation
• Premature Ovarian Failure
• Primary Ovarian Insufficiency
• Syndrome
• Turner Syndrome

Intervention

Procedure:
• Ovarian tissue cryopreservation
Laparoscopic unilateral oophorectomy followed by cryopreservation of ovarian cortex tissue

Locations

Country	Name	City	State
Netherlands	Radboud university medical center. Department Obstetrics & Gynaecology.	Nijmegen	Gelderland

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University Medical Center

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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, Söderström-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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Study participation rate	The willingness of girls with TS to perform a unilateral oophorectomy for fertility preservation (i.e. the study participation rate)	Up to 3 years after inclusion
Other	Eligible participants	The number of eligible participants	Up to 3 years after inclusion
Other	Age	The age of the participant	Up to 3 years after inclusion
Other	Buccal cells versus peripheral lymphocytes	The incidence of somatic mosaicism (i.e. buccal cells versus peripheral lymphocytes)	Up to 3 years after inclusion
Other	Ovarian cells versus peripheral lymphocytes	The incidence of germ cell mosaicism (i.e. ovarian cells versus peripheral lymphocytes and buccal cells)	Up to 3 years after inclusion
Other	Serum hormone levels	Serum hormone levels (i.e. FSH, Luteinizing hormone (LH), AMH, E2, inhibin B)	Up to 3 years after inclusion
Other	Complication rate	The number of complications related to the laparoscopic procedure	Up to 1 year after the laparoscopic procedure
Other	Influence of laparoscopic oophorectomy on puberty and/or menarche	The incidence of puberty and/or menarche after laparoscopic oophorectomy	Up to 10 years after the laparoscopic procedure
Other	Incidence of spontaneous pregnancies	The incidence of spontaneous pregnancies after laparoscopic oophorectomy	Up to 45 years after the laparoscopic procedure
Other	Restoration of ovarian function after auto transplantation of ovarian tissue	The incidence of menstruation cycle recovery after auto transplantation of cryopreserved-thawed ovarian tissue in the future	Up to 2 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Other	Pregnancies after auto transplantation of ovarian tissue	The incidence of pregnancies after auto transplantation of cryopreserved-thawed ovarian tissue in the future	Up to 2 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Other	Ongoing pregnancies after auto transplantation of ovarian tissue	The incidence of ongoing pregnancies after auto transplantation of cryopreserved-thawed ovarian tissue in the future	Up to 2 years and 3 months after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Other	Miscarriages after auto transplantation of ovarian tissue	The number of miscarriages after auto transplantation of cryopreserved-thawed ovarian tissue in the future	Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Other	Time to pregnancy after auto transplantation of ovarian tissue	Time to pregnancy after auto transplantation of cryopreserved-thawed ovarian tissue in the future	Up to 2 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Other	Time to live birth after auto transplantation of ovarian tissue	Time to live birth after auto transplantation of cryopreserved-thawed ovarian tissue in the future	Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Primary	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.
Primary	Number of primordial follicles (proximate)	The number of primordial follicles found in the ovarian tissue	Within 1 month after ovarian tissue cryopreservation
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.