FEMALE FERTILITY PRESERVATON OPTIONS

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

Standard of care options

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

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, https://www.cincinnatichildrens.org/service/f/fertility-preservation/females

Experimental options

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.

Ovarian Tissue Cryopreservation Jadoul P et al. Hum. Reprod. Update 2010;16:617-630 - 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

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;12:519-535

~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

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

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

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)