1. FEMALE FERTILITY PRESERVATON OPTIONS

2. Female Fertility Option
Standard of Care Options
Oocyte / Embryo Cryopreservation
Ovarian Transposition
Experimental Options
GnRH Analogues
Ovarian Cryopreservation

3. Standard of care options

4. Oocyte & Embryo Cryopreservation Consideration in Pediatric & Adolescent Patients
Standard of Care options in post-pubertal female patients
Oocyte cryopreservation non-experimental (ASRM 2012)
Controlled ovarian stimulation  multiple mature oocytes
Success rates published by clinic
Society for Assisted Reproductive Technologies
Average: 33-52% live birth rates
Limited adolescent and oncology specific data
Barriers: Time/delay in treatment, cost/insurance coverage, concern for procedural technique or side effects
Consideration: Adolescent friendly alterations
Change in OC to standard of care removes previous barriers (requirement of partner, donor sperm)
Monitoring during ovarian stimulation is traditionally completed with TVUS
Oocyte retrieval completed TV (minimally invasive, but requires sedation or anesthesia)
Oocytes frozen or can be combined in-vitro wit partner/donor sperm to create embryo’s then frozen
Barriers
-TIME: More recent protocol stimulate in luteal phase, studies show consultation/retrieval in two weeks
-COST: Many insurance do not cover fertility, those that do have limited definition that does not cover these patients
- Connecticut – first state to enact law for fertility preservation coverage. Changed definition of “infertility” to remove “otherwise healthy” and include “medically necessary”
- Patient assistance programs for oncology patients (medications, shipping and long-term storage fee discounts)
-PROCEDURAL
Some true vs untrue concerns (pt and provider education important)
Many clinics consider “adolescent friendly” alternatives such a small vaginal probes or abdominal ultrasound follicular monitoring, waiting room alterations
Mature oocyte cryopreservation: A Guideline. Fertil Steril 2013;99:37–43

5. Ovarian Transposition
Pelvic or abdominal radiation with significant risk of amenorrhea and subsequent infertility.
greater than 15 Gy in prepubertal girls
greater than 10 Gy in postpubertal girls
Surgically move ovaries out of the radiation field
Success rates
50-90% reduction in radiation to the ovary
30-50% maintenance of ovarian function
Unknown fertility preservation success
Not well study in pediatric population
Often, the ovaries are moved to a lateral location in the paracolic gutter by a laparoscopic technique
unilateral or bilateral oophoropexy can be performed depending on the location of disease and anticipated site of radiotherapy
Complications can include ovarian torsion, bowel obstruction, and abdominal pain, general LSC risks (bleeding, infection, injury)
Estes S End Met 2015,

6. Experimental options

7. GnRH Analogues Mimic pre-pubertal “quiescent” ovary
Problems with early study design
More recent studies improve design
3 show decreased amenorrhea
3 show no protection of ovarian reserve (2 stopped earlier)
2013 ASCO Guidelines: Insufficient evidence
POEMS Trial (2015)
Breast Cancer + Goserelin
Reduction in ovarian failure (p = 0.04)
Increased odds ratio for pregnancy (p = 0.03)
The use of GnRH analogues (both agonists and antagonists) to lessen the effect of chemotherapy on follicular depletion has long held appeal as this is much less invasive compared to the cryopreservation of reproductive tissue
Most early studies evaluating their efficacy have been hampered by small numbers, retrospective design and inconsistent outcome measures, making it difficult to draw definitive conclusions.
More recently, prospective, randomized studies have been undertaken to address this question.
- Three such studies in young adult women with breast cancer demonstrated decreased rates of amenorrhea in those patients who received GnRH analogues
- Three trials in young adult patients with breast cancer and Hodgkin lymphoma demonstrated no protection of ovarian reserve using GnRH analogues.
- Two of the studies were stopped prematurely when interim analyses demonstrated futility
The 2013 ASCO guidelines recommend that patients be informed that there is insufficient evidence showing that ovarian suppression via the use of GnRH analogues protects fertility and should not be relied upon for this indication
Most recently, the POEMS trial (Prevention of Early Menopause)
-Randomized breast cancer patients to either standardized chemotherapy or standardized chemotherapy plus goserelin
-That trial demonstrated a significant reduction in ovarian failure (defined as amenorrhea of six months plus elevated FSH at two years).
-They also demonstrated a significantly increased odds ratio (OR = 2.22, 95% CI: 1.00–4.92, p = 0.05) for pregnancy in the experimental arm.
- This is the first study to demonstrate a difference in pregnancy rate (Stand 12/Gos 22). The impact of this study on future guideline recommendations remain to be seen.
Levine J Children 2014, Loren AW et al J Clin Oncol 2013, Moore HCF et al J Clin Onc 2014.

8. Ovarian Tissue Cryopreservation
Jadoul P et al. Hum. Reprod. Update 2010;16:
- Removal whole or portion of ovary
Separate the ovarian cortex separated from the medulla
Cut into small thin strips (20 x 5 x 1 mm) and cryopreserved
Slow freeze standard (initial studies show vitrification may be a favored approach, outcome studies needed prior replacing as standard)
Temporary then long term storage
Ovarian Tissue Cryopreservation: A Committee Opinion. Fertil Steril. 2014;101:1237–43

9. Orthotopic Transplantation
Ovarian Fossa
Contralateral Ovary
Donnez et al. Frontiers in Bioscience 2012, Donnez et al. Fert Steril 2012
Orthotopic (pelvic) transplantation (Ovarian Fossa, Contralateral Ovary) – all births this method
Heterotopic (extra-pelvic) transplantation (forearm, abdominal wall) – no live births
Future: IVM (isolate & mature oocytes from ovarian tissue for use in IVF either at time of removal or after OTC)
- Sx (no live births), after cryo (only in animal models)
- Decrease / eliminate concern for transplanting back oncologic cells
Donnez J et al. Hum. Reprod. Update 2006;12:

10. ~85 live births (all from Orthotopic transplantation)
Heterotopic transplantation – no pregnancies
Future: IVM (no human studies past M2)
All but two pregnancies in adult women
Therefore, this technique remains experimental as defined by ASRM
OTC Safety:
In Jadual Study (Belgium), 30% < 18, 15% pre-pubertal
Overall complications 140 pts): 5 minor, 1 major requiring repeat sx for bleeding after LSC (1 death in all of literature following OTC procedure related)
Jadual study – 10 % deceased rate ( 13.5% in pts < 18 yo)
Utilization rates ~4% (compared to <10% in semen studies)\
96% patients satisfied with procedures (including patients who did require re-implantation – donated or discarded tissue)
LB to cover:
Initially difficult to define success, as literature was mostly case reports or series without defined denominator
Several more recent outline their denominator - Success rates described at ~20-30% after autotransplantation of frozen-thawed ovarian cortex. Is standard of care in Isreal.
However, These are based on small numbers (N = 20, 32, 49, 60), variable definitions of POI between studies (hormonal vs lack of menses), and some concern has been voiced for inability of assure pregnancies were not stimulated from native ovary, as pregnancies have been reported in patients with POI.
Donnes et al., 2013, 2016; Dittrich et al., 2015; Jensen et al., 2015; Meirow et al., Van der en et al., 2016

11. CCHMC OTC Protocols Purposely left broad
Females 1 month to 41 years of age
Undergo surgery, chemotherapy, drug treatment, and/or radiation for the treatment or prevention of a medical condition or malignancy expected to result in permanent and complete loss of subsequent ovarian function
Or, have a medical condition or malignancy that requires removal of all or part of one or both ovaries.
Is not a candidate for or chooses not to utilize embryo or oocyte banking.
Serum FSH levels ≤ 20 mIU/ml.
Purposely left broad
No restrictions based on risk assessment
Allows for case by case evaluation
Along with stipulations for health for consent and surgery, no masses on ovary

12. Age ranged from 0.6 years to 33.2 years old
OTC at CCHMC
N = 52
Age ranged from 0.6 years to 33.2 years old
Median age 10.7 years old

13. OTC at CCHMC N = 52 (n= 52) Diagnosis Types Malignancy 25 Solids 18
Liquids 2
Neuro-Onc 5
Hematologic Disorder 20
Immune Deficiency 4
Metabolic Disorder 1
Other
Treatment
Chemo Alone 10
Chemo + Radiation 11
Bone Marrow Transplant 31
Myeloablative 17
RIC 14
Infertility Risk
High 47
Intermediate 5
Low
Menarchal Status
Premenarchal 34
Post-menarchal 18
Time < 2 weeks 11
Time > 2 weeks 7
Time Available
< 1 week 8
1-2 weeks 15
2-6 weeks 19
> 6 weeks 10
Hematologic: FA, Sickle Cell, thallasemia
Immune: HLH
Other: Bone Marrow Failure, Juvenile Arthritis with macrophage activation
Deaths: During this data collection 5/52 (9.6%)
Benoit J, Hoefgen HR, et al., Publication Pending
(n= 52)