Study Description:
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.
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.
Lack of follicles/gametes in the gonadal tissue will confirm that GTC is not a
viable option for fertility preservation for these populations.
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.
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.
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:
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.
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:
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.
Correlation of follicle/gamete density and quality with markers such as age, AMH,
condition.
Comparison of hormone levels such as AMH, FSH, LH, and Estradiol between patients
and controls.
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.
