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

  • STATUS
    Recruiting
  • End date
    Jul 31, 2030
  • participants needed
    100
  • sponsor
    Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Updated on 22 September 2022
follicle stimulating hormone
premature
infertility
ovarian failure

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.

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.

Details
Condition Ovarian Disfunction, Post-menarcheal Adolescents, Turner Syndrome, Galactosemia
Clinical Study IdentifierNCT04948658
SponsorEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Last Modified on22 September 2022

Eligibility

Yes No Not Sure

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)
Adolescent females up to age 21 years old, who have undergone menarche and are
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
Stated willingness to comply with all study procedures and availability for the
duration of the study
subsequently diagnosed with premature ovarian insufficiency and their last menstrual period
Ability of subject, parents or guardian to understand and the willingness to sign a
occurred within 2 years of presentation. Diagnosis of POI is based on 2 elevated FSH
written informed consent document
concentrations obtained over 1 month apart
Or
Adolescents who have diminished ovarian reserve who respond poorly to ovarian
stimulation for egg freezing

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
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