Gonadal Tissue Freezing for Fertility Preservation in Individuals at Risk for Ovarian Dysfunction and Premature Ovarian Insufficiency

• ClinicalTrials.gov Identifier: NCT04948658
• Recruitment Status: Recruiting
• First Posted: July 2, 2021
• Last Update Posted: August 2, 2022
• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )

Study Description

Brief Summary:

Background:

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 ovarian tissue allows for fertility preservation.

Objective:

To find out why females with certain conditions have can have premature ovarian insufficiency (POI or early menopause) and trouble getting pregnant and if freezing the tissue from their ovary will help them have their own child in the future.

Eligibility:

Females aged 4-12 who have Turner Syndrome or galactosemia. Also, females aged 13 21 with premature ovarian insufficiency.

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 will have surgery to remove an ovary. 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 ovary (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.

Condition or disease
Ovarian Disfunction; Post-menarcheal Adolescents; Turner Syndrome; Galactosemia

Detailed Description:

Study Description:

Ovarian tissue cryopreservation and evaluation in individuals with Turner Syndrome, individual with Turner syndrome with Y material who undergo prophylactic gonadectomy, galactosemia, post- menarcheal adolescents with recent premature ovarian insufficiency, and adolescents 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, which are associated with acute or chronic effects on ovarian function and reproduction.

Objectives:

Primary Objectives: After initial evaluation of number and quality of follicles before and after cryopreservation and thawing, the remaining tissue will be utilized to perform research regarding mechanisms of follicle loss in Turner and galactosemia as well as post-menarcheal adolescent individuals with a recent diagnosis of POI

1. We will perform single cell/nucleus RNA sequencing on the tissue collected from study participants and ovaries from cadaveric organ donors on cardiopulmonary support.
2. We will perform single cell/nucleus RNA sequencing on fresh ovarian tissue and compare it to frozen and thawed tissue

Hypothesis: Single cell/nucleus RNA sequencing from tissue obtained from ovaries 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 ovarian tissue as well as the effects after freezing and thawing) of ovarian tissue cryopreservation (OTC) for fertility preservation in children with increased risk of loss of ovarian function due to Turner syndrome (with or without Y material) or galactosemia and post-menarcheal adolescents with a recent development of premature ovarian insufficiency (POI) or with diminished ovarian reserve (those who do not respond to ovarian stimulation for oocyte cryopreservation due to lower follicle counts).

1. The feasibility will be evaluated through evaluation of number and quality of follicles found in the tissue prior to freezing and after thawing.

2. Lack of follicles in the ovarian tissue will confirm that OTC is not a viable option for this

   population.

3. An attempt to correlate laboratory and imaging markers with follicle presence and number will be made.

Hypothesis: Young individuals with Turner syndrome and galactosemia and adolescents with recent POI, harbor populations of follicles which may be preserved through ovarian tissue cryopreservation for future fertility.

1. There will be a variety of follicular findings which will correlate with patient s anti-Mullerian hormone (AMH), age and underlying condition.
2. 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 single cell/nucleus RNA

sequencing will be performed in order to assess gene expression before and after treatment

Hypothesis: Primordial follicles within ovarian 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: Single cell/nucleus RNA sequencing will be performed on tissues of

   affected individuals and compared to age matched controls who will be 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. Single cell/nucleus RNA 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 in the ovaries of individuals with Turner syndrome (with or without Y material), galactosemia and post-menarcheal adolescent with premature ovarian insufficiency or with diminished ovarian reserve (those who do not respond to ovarian stimulation for oocyte cryopreservation due to lower follicle counts)
2. Correlation of follicle 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.

Tertiary Endpoint

-Evaluate changes in single cell/nucleus RNA sequencing in tissue before and after treatment with primordial follicle inhibitors and activators. The remaining tissue will be cryopreserved for future experiments.

Study Design

• Study Type: Observational
• Estimated Enrollment: 100 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Gonadal Tissue Freezing for Fertility Preservation in Individuals at Risk for Ovarian Dysfunction and Premature Ovarian Insufficiency
• Actual Study Start Date: September 13, 2021
• Estimated Primary Completion Date: July 31, 2030
• Estimated Study Completion Date: July 31, 2030

Groups and Cohorts

Group/Cohort
Adolescents with DOR; Adolescents who have diminished ovarian reserve who respond poorly to ovarian stimulation for egg freezing
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.
Turner Syndrome and galactosemia; Individuals with Turner Syndrome and galactosemia prior to menarche aged 4 years to 12 years who have not demonstrated signs of premature ovarian insufficiency (one FSH>25 IU/L)
Turner Syndrome with Y material; Children and adolescents who have Turner syndrome with Y material and undergo prophylactic gonadectomy.

Outcome Measures

Primary Outcome Measures :

1. Single cell/nucleus RNA sequencing [ Time Frame: before and after cryopreservation ]
   Single cell/nucleus RNA sequencing on fresh compared to frozen and thawed tissue. This will assess what transcription changed occur due to the freezing process.
2. Tissue for research [ Time Frame: before and after cryopreservation ]
   initial evaluation of number and quality of follicles before and after cryopreservation

Secondary Outcome Measures :

1. Correlation of follicle density and quality with markers such as age, AMH, condition. [ Time Frame: before and after cryopreservation ]
   Correlation of follicle density and quality with markers such as age, AMH, condition.
2. density and quality of follicles in the ovaries [ Time Frame: before and after cryopreservation ]
   Evaluation of density and quality of follicles in the ovaries of girls with Turner syndrome, galactosemia and post-menarcheal adolescent with premature ovarian insufficiency before and after cryopreservation and thawing
3. Compare hormone levels [ Time Frame: before and after cryopreservation ]
   Comparison of hormone levels such as AMH, FSH, LH, and Estradiol between patients and controls.
4. Evaluate changes in single cell/nucleus RNA sequencing [ Time Frame: before and after cryopreservation ]
   Evaluate changes in single cell/nucleus RNA sequencing in tissue before and after treatment with primordial follicle inhibitors and activators.

Eligibility Criteria

• Ages Eligible for Study: 4 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Individuals with Turner Syndrome and galactosemia prior to menarche aged 4 years to 12 years, who have not demonstrated signs of premature ovarian insufficiency (FSH>25 IU/L). Individuals with Turner Syndrome with Y chromosome material who undergo prophylactic gonadectomy. Adolescent females age 13 to 21 years old who have undergone menarche and are subsequently diagnosed with premature ovarian insufficiency with their last menstrual period having occurred within 2 years of presentation. Adolescents with diminished ovarian reserve who have contraindication to ovarian stimulation as well as those with diminished ovarian reserve who did not respond to ovarian stimulation.

Criteria

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following

criteria:

- Individuals with Turner Syndrome and galactosemia prior to menarche aged 4 years to 12 years who have not demonstrated signs of premature ovarian insufficiency (one FSH>25 IU/L) whose families seek to store ovarian tissue for possible future use.

Or

- Children and adolescents who have Turner syndrome with Y material and undergo prophylactic gonadectomy.

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

• Adolescents who have diminished ovarian reserve who respond poorly to ovarian stimulation for egg freezing.
• 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:

An individual who meets any of the following criteria will be excluded from participation in this study:

• Females older than 7 years with psychological, psychiatric, or other conditions which prevent giving fully informed consent or assent.
• Females 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
• Females 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

Contacts and Locations

Contacts

Contact: Veronica Gomez-Lobo, M.D.; (301) 435-7567; veronica.gomez-lobo@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov

Sponsors and Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Veronica Gomez-Lobo, M.D.; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Ethics Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org. 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. Review.

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.

• Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• ClinicalTrials.gov Identifier: NCT04948658
• Other Study ID Numbers: 10000106; 000106-CH
• First Posted: July 2, 2021
• Last Update Posted: August 2, 2022
• Last Verified: July 26, 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: .We are trying to figure out if we want to share IPD.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) ):

OVARIAN FUNCTION; follicle loss; Natural History

Additional relevant MeSH terms:

Galactosemias; Turner Syndrome; Gonadal Dysgenesis; Menopause, Premature; Primary Ovarian Insufficiency; Ovarian Diseases; Disorders of Sex Development; Urogenital Abnormalities; Sex Chromosome Disorders of Sex Development; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Sex Chromosome Disorders; Chromosome Disorders; Genetic Diseases, Inborn; Gonadal Disorders; Endocrine System Diseases; Adnexal Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Metabolic Diseases