Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Turner Syndrome; Premature Ovarian Failure; Fertility Preservation; Live Birth; Ovarian Tissue Cryopreservation
• Intervention / Treatment: Procedure: Ovarian tissue cryopreservation

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.

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500HB
      • Radboud university medical center. Department Obstetrics & Gynaecology.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Single cohort	Procedure: Ovarian tissue cryopreservation; Laparoscopic unilateral oophorectomy followed by cryopreservation of ovarian cortex tissue

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Eligible participants	The number of eligible participants	Up to 3 years after inclusion
Age	The age of the participant	Up to 3 years after inclusion
Buccal cells versus peripheral lymphocytes	The incidence of somatic mosaicism (i.e. buccal cells versus peripheral lymphocytes)	Up to 3 years after inclusion
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
Serum hormone levels	Serum hormone levels (i.e. FSH, Luteinizing hormone (LH), AMH, E2, inhibin B)	Up to 3 years after inclusion
Complication rate	The number of complications related to the laparoscopic procedure	Up to 1 year after the laparoscopic procedure
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
Incidence of spontaneous pregnancies	The incidence of spontaneous pregnancies after laparoscopic oophorectomy	Up to 45 years after the laparoscopic procedure
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Kathrin Fleischer, MD, PhD, Head Department of Reproductive Medicine, Gynaecologist/Subspecialist Reproductive Medicine

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Estimated): November 1, 2071
• Study Completion (Estimated): November 1, 2071

Study Registration Dates

• First Submitted: November 22, 2017
• First Submitted That Met QC Criteria: December 20, 2017
• First Posted (Actual): December 21, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 14, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Cardiovascular Diseases; Pathologic Processes; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Heart Diseases; Genetic Diseases, Inborn; Disease; Genital Diseases, Female; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Disorders of Sex Development; Urogenital Abnormalities; Sex Chromosome Disorders; Chromosome Disorders; Sex Chromosome Disorders of Sex Development; Syndrome; Menopause, Premature; Primary Ovarian Insufficiency; Turner Syndrome; Gonadal Dysgenesis
• Other Study ID Numbers: NL57738.000.16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No