Clinical trial NCT03381300: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Fertility Preservation
Ovarian Tissue Cryopreservation
Turner Syndrome
Live Birth
Premature Ovarian Failure
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2017-12-21
Enrollment: 106
Sex: FEMALE
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Live birth ratio (LBR) (main outcome)
timeFrame: Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
measure: Number of primordial follicles (proximate)
timeFrame: Within 1 month after ovarian tissue cryopreservation
Secondary outcomes:
measure: Patient's age versus LBR
timeFrame: Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
measure: Patient's genotype versus LBR
timeFrame: Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
measure: Patient's Anti-Müllerian hormone (AMH) level versus LBR
timeFrame: Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
measure: Patient's Follicle-stimulating hormone (FSH) level versus LBR
timeFrame: Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue, and up to 45 years after ovarian tissue cryopreservation.
Other outcomes:
measure: Study participation rate
timeFrame: Up to 3 years after inclusion
measure: Eligible participants
timeFrame: Up to 3 years after inclusion
measure: Age
timeFrame: Up to 3 years after inclusion
measure: Buccal cells versus peripheral lymphocytes
timeFrame: Up to 3 years after inclusion
measure: Ovarian cells versus peripheral lymphocytes
timeFrame: Up to 3 years after inclusion
measure: Serum hormone levels
timeFrame: Up to 3 years after inclusion
measure: Complication rate
timeFrame: Up to 1 year after the laparoscopic procedure
measure: Influence of laparoscopic oophorectomy on puberty and/or menarche
timeFrame: Up to 10 years after the laparoscopic procedure
measure: Incidence of spontaneous pregnancies
timeFrame: Up to 45 years after the laparoscopic procedure
measure: Restoration of ovarian function after auto transplantation of ovarian tissue
timeFrame: Up to 2 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
measure: Pregnancies after auto transplantation of ovarian tissue
timeFrame: Up to 2 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
measure: Ongoing pregnancies after auto transplantation of ovarian tissue
timeFrame: Up to 2 years and 3 months after auto transplantation of cryopreserved-thawed ovarian cortical tissue
measure: Miscarriages after auto transplantation of ovarian tissue
timeFrame: Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
measure: Time to pregnancy after auto transplantation of ovarian tissue
timeFrame: Up to 2 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
measure: Time to live birth after auto transplantation of ovarian tissue
timeFrame: Up to 3 years after auto transplantation of cryopreserved-thawed ovarian cortical tissue
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud university medical center. Department Obstetrics & Gynaecology.
state: Gelderland
Study officials:
affiliation: Head Department of Reproductive Medicine, Gynaecologist/Subspecialist Reproductive Medicine
name: Kathrin Fleischer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.