Gonadal Tissue Freezing for Fertility Preservation in Individuals at Risk for Ovarian Dysfunction, Premature Ovarian Insufficiency and Clinically Indicated Gonadectomy
NCT ID: NCT04948658
Last Updated: 2026-01-26
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
200 participants
OBSERVATIONAL
2021-09-13
2030-07-31
Brief Summary
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Turner Syndrome, galactosemia, and premature ovarian insufficiency are all conditions that may make it very hard or impossible for a person to become pregnant and have their own child. Researchers want to learn more about why this happens and if freezing Gonadal tissue allows for fertility preservation.
Objective:
To find out why people with certain conditions have can have premature ovarian insufficiency (POI or early menopause) and individuals with variations in sex characteristics have trouble getting pregnant and if freezing the gonads tissue from them will help to have their own child in the future.
Eligibility:
Individuals aged 2-21 who have Turner Syndrome or galactosemia. Also, females aged 13-21 with premature ovarian insufficiency, individuals with variations in sex characteristics, and individuals 2-35 receiving high-risk gonadotoxic therapy
Design:
Participants will be screened with a medical history.
Participants may have a physical exam and blood tests. Their body measurements may be taken. These include weight, height, arm span, skin fold, and sitting height. They may fill out surveys about their quality of life, body image, and health.
Participants may have a transabdominal pelvic ultrasound. A probe will be placed on their belly and will take pictures of the organs in the pelvis. They may have a transvaginal pelvic ultrasound performed while asleep in the operating room if needed.
Participants may have surgery to remove an gonads and skin biopsy. The removed tissue will be frozen and stored. The tissue will have to be stored for many years. NIH will pay to store the tissue for 1 year. After that, participants will have to pay for storage.
A piece of the gonads (no more than 20%) will be used for research
Travel, lodging and meals for participants traveling greater than 50 miles will be reimbursed based off the government rate. Local participants will not be reimbursed.
Participants will have a checkup 6 weeks after surgery one or more follow-up visits 6-18 months after surgery. They may have phone follow-up every 12-24 months after surgery.
Participation will last 30 years.
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Detailed Description
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Gonadal tissue cryopreservation will be evaluated in individuals with Turner Syndrome, galactosemia, post-menarcheal adolescents with recent premature ovarian insufficiency, and children/adolescents conditions associated with POI and with diminished ovarian reserve (DOR) who have contraindication to ovarian stimulation as well as those with diminished ovarian reserve who did not respond to ovarian stimulation, and individuals with variations in sex characteristics (VSD or differences in sex development, DSD) including those with Turner syndrome with Y chromosome material and those with conditions that require high risk gonadotoxic therapy.
Objectives:
Primary Objectives: After initial evaluation of number and quality of follicles/gametes, the remaining tissue will be utilized to perform research regarding mechanisms of follicle/gametes loss in the included conditions.
a. We will perform next generation sequencing on the tissue collected from study participants and ovaries from cadaveric organ donors on cardiopulmonary support. Additionally, some ovarian tissue from patients undergoing gonadotoxic therapy will function as controls.
Hypothesis: next generation sequencing from tissue obtained from gonads in individuals with these conditions will differ significantly from that of controls. Such differences may allow for further hypothesis development regarding the underlying mechanism of follicle loss and/or dysfunction in individuals with these conditions.
Secondary Objective: This protocol is designed to evaluate the feasibility (meaning a reasonable expectation of future fertility based on the anatomy, histology, and physiology of fresh gonadal tissue as well as the effects after freezing and thawing) of gonadal tissue cryopreservation (GTC) for fertility preservation in children with increased risk of loss of gonadal function due to underlying genetic conditions including Turner syndrome or galactosemia and post-menarcheal adolescents with a recent development of premature ovarian insufficiency (POI) or children/adolescents with conditions associated with POI and presenting with diminished ovarian reserve (based on laboratory findings of low AMH (\<1.0 ng/mL) and/or mildly elevated FSH (\>10 U/L) or those who do not respond to ovarian stimulation for oocyte cryopreservation due to lower follicle counts) or individuals with variations in sex characteristics.
1. The feasibility GTC as a fertility preservation option in these individuals will be evaluated through evaluation of number and quality of follicles/gametes found in the tissue prior to freezing and after thawing.
2. Lack of follicles/gametes in the gonadal tissue will confirm that GTC is not a viable option for fertility preservation for these populations.
3. An attempt to correlate laboratory and imaging markers with follicle/gamete presence and number will be made.
b. Hypothesis: Young individuals with Turner syndrome, variations of sex characteristics, classic galactosemia and adolescents with recent POI, and children/adolescents with underlying conditions associated with POI presenting with DOR harbor populations of follicles/gametes which may be preserved through gonadal tissue cryopreservation for future fertility. There will be a variety of follicular findings which will correlate with patient s anti-Mullerian hormone (AMH), age and underlying condition.
c. Depending on their underlying condition, individuals with VSC will have gametes (follicles and/or spermatogonia).
d. Loss of follicles with cryopreservation and thawing will be similar to that of non-affected individuals.
Tertiary Objectives:
Research regarding inhibition and activation of follicles within the tissue will be undertaken.
1. Tissue will be treated with known inhibitors and activators and next generation sequencing will be performed in order to assess gene expression before and after treatment.
2. To create a national database of human ovarian tissue of individuals who are undergoing OTC in order to elucidate short and long term outcomes including complication and reproductive health parameters.
Hypothesis: Primordial follicles within gonadal tissue in individuals with these conditions may be inhibited from activating. Such techniques may allow for a decrease in follicle loss with freezing and thawing as well as possible future development of novel treatments to prevent accelerated follicle loss in individuals and adolescent affected by these conditions. Promoting follicle activation prior to re-implantation of the tissue may improve the possibility of achieving pregnancy after tissue re-implantation
Endpoints:
Primary Endpoints:
1. Tissue for research: Next generation sequencing will be performed on tissues of affected individuals and compared to age matched controls: patients who undergo GTC for solid organ tumors far from the reproductive system or cadaveric organ donors on cardiopulmonary support. This will allow for specific cellular type comparisons within the ovary and exploratory research regarding possible mechanisms of follicle loss in these populations.
2. Next generation sequencing on fresh compared to frozen and thawed tissue. This will assess what transcription changed occur due to the freezing process.
Secondary Endpoint:
1. Evaluation of density and quality of follicles/gametes in the gonads of individuals with increased risk of loss of gonadal function due to underlying genetic conditions including Turner syndrome or galactosemia and post-menarcheal adolescents with a recent development of premature ovarian insufficiency (POI) or children/adolescents with conditions associated with POI and presenting with diminished ovarian reserve (based on laboratory findings of low AMH (\<1.1 ng/mL) and mildly elevated FSH (10-25 U/L) or those who do not respond to ovarian stimulation for oocyte cryopreservation due to lower follicle counts) or individuals with variations in sex characteristics.
2. Correlation of follicle/gamete density and quality with markers such as age, AMH, condition.
3. Comparison of hormone levels such as AMH, FSH, LH, and Estradiol between patients and controls.
4. Long term data regarding surgical complications
Tertiary Endpoint:
-Evaluate changes in single next generation sequencing in tissue before and after treatment with primordial follicle inhibitors and activators. The remaining tissue will be cryopreserved for future experiments.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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Adolescents with DOR
Adolescents with diminished ovarian reserve (DOR) who respond poorly to ovarian stimulation for egg freezing.
No interventions assigned to this group
Adolescents with POI
Adolescent females up to age 21 years old, who have undergone menarche and are subsequently diagnosed with POI and their last menstrual period occurred within 2 years of presentation.
No interventions assigned to this group
Individuals receiving high-risk gonadotoxic therapy
Individuals (2-35 years) receiving high-risk gonadotoxic therapy at the NIH Clinical Center who are at high risk for developing premature ovarian insufficiency and infertility.
No interventions assigned to this group
Individuals with variations in sex characteristics (or differences in sex development, DSD)
Individuals with variations in sex characteristics (or differences in sex development, DSD) who undergo gonadectomy for clinical indications.
No interventions assigned to this group
Turner Syndrome and galactosemia
Individuals with Turner Syndrome prior to menarche aged 2 years to 12 years, who have not previously demonstrated signs of premature ovarian insufficiency (FSH\>25 IU/L).
No interventions assigned to this group
Turner Syndrome with Y material
Children and adolescents who have Turner syndrome with Y material and undergo prophylactic gonadectomy.
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
-Individuals with Turner Syndrome prior to menarche aged 2 years to 12 years whose families seek to store ovarian tissue for possible future use.
Or
Individuals with galactosemia (age 2-21)
Or
Adolescent females up to age 21 years old, who have undergone menarche and are subsequently diagnosed with premature ovarian insufficiency and their last menstrual period occurred within 2 years of presentation. Diagnosis of POI is based on 2 elevated FSH concentrations obtained over 1 month apart.
Or
Children or adolescents who have diminished ovarian reserve based on laboratory findings or who respond poorly to ovarian stimulation for egg freezing.
Or
Individuals with variations in sex characteristics (or differences in sex development, DSD) including Turner syndrome with Y chromosome material who undergo prophylactic gonadectomy for clinical indications.
Or
Individuals (2-35 years) receiving high-risk gonadotoxic therapy at the NIH Clinical Center who are at high risk for developing premature ovarian insufficiency and infertility.
* Stated willingness to comply with all study procedures and availability for the duration of the study.
* Ability of subject, parents, or guardian to understand and the willingness to sign a written informed consent document.
Exclusion Criteria
* Individuals older than 7 years with psychological, psychiatric, or other conditions which prevent giving fully informed consent or assent.
* Individuals with a pelvic mass tumor noted on pre-operative ultrasound, will undergo usual care for the underlying condition and will not undergo oophorectomy for ovarian tissue cryopreservation.
* Individuals whose underlying medical condition significantly increases their risk of complications from anesthesia and surgery.
* Females with POI due to chemotherapy or radiation treatment
* Pregnancy or lactation
* Individuals with VSC who choose to retain gonads after clinical consulting.
* Individuals with Turner Syndrome who have an undetectable AMH based on testing laboratory reference range.
2 Years
35 Years
ALL
No
Sponsors
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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NIH
Responsible Party
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Principal Investigators
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Veronica Gomez-Lobo, M.D.
Role: PRINCIPAL_INVESTIGATOR
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Locations
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National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Countries
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Central Contacts
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Facility Contacts
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For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Role: primary
References
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Ethics Committee of the American Society for Reproductive Medicine. Electronic address: [email protected]. Fertility preservation and reproduction in patients facing gonadotoxic therapies: an Ethics Committee opinion. Fertil Steril. 2018 Aug;110(3):380-386. doi: 10.1016/j.fertnstert.2018.05.034.
Martinez F; International Society for Fertility Preservation-ESHRE-ASRM Expert Working Group. Update on fertility preservation from the Barcelona International Society for Fertility Preservation-ESHRE-ASRM 2015 expert meeting: indications, results and future perspectives. Fertil Steril. 2017 Sep;108(3):407-415.e11. doi: 10.1016/j.fertnstert.2017.05.024. Epub 2017 Jul 21.
Andersen ST, Pors SE, Poulsen LC, Colmorn LB, Macklon KT, Ernst E, Humaidan P, Andersen CY, Kristensen SG. Ovarian stimulation and assisted reproductive technology outcomes in women transplanted with cryopreserved ovarian tissue: a systematic review. Fertil Steril. 2019 Nov;112(5):908-921. doi: 10.1016/j.fertnstert.2019.07.008. Epub 2019 Oct 6.
Related Links
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NIH Clinical Center Detailed Web Page
Other Identifiers
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000106-CH
Identifier Type: -
Identifier Source: secondary_id
10000106
Identifier Type: -
Identifier Source: org_study_id
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