Fertility Preservation in Children Joseph G. Schenker MD. FRCOG. FACOG.FIAHR.FIAPM Hebrew University –Hadassah Medical Centre Jerusalem,Israel President of International Academy of Human Reproduction

Presently Medical Professionals must Focused on Treating Cancers in Children to Extend their Lives with Concern over Preserving their Fertility. Fertility Preservation in PREPUBERTAL CHILDREN is a particularly Complicated Arena. The Medical,Ethical and Legal Issues will be Discussed

Childhood Cancer Rate National Cancer Institute 2012 UP TO 80% SURVIVE THE PRIMARY CANCER

Survival rate Leukemia

Cancer Therapy

Ovarian Failure Rate - Disease Oriented Leukemia Lymphoma Breast AML NHL Hodgkin’s Cancer Leukemia Lymphoma Breast AML NHL Hodgkin’s Cancer

Alkylatingagents Antibiotics Plant PlantAlkaloids Odds Ratio Platine AntiMetabolites Ovarian Failure by Drug Age Adjusted Odds Ratio Exposed- vs.- Unexposed

The Risk of Ovarian Failure Dependent on Treatment Patient Age AGE Fertility % CHEMO CHEMO +TBI TBI

Effect of Chemotherapy On Reproduction Is determined by the Patient's Sex Age Drug used Dose administered

Cancer Treatments by Risk of Gonadotoxicity High Risk (+ 80%) Whole-body irradiation Localised radiotherapy: pelvic or testicular Chemotherapy conditioning for bone marrow transplantation Hodgkin’s disease: Treatment with alkylating drugs Soft-tissue sarcoma: stage IV Ewing’s sarcoma: metastatic Low Risk (‹ 20%) Acute lymphoblastic leukemia Wilms’ tumor Soft-tissue sarcoma: stage I Germ cell tumors Retinoblastoma Brain tumor: surgery only cranial irradiation ‹ 24 Gy G Ryan In: Ethical Dilemma in ART Ed. JG Schenker

Gender-Tailored Therapy Males are more Susceptible to the Damage of Chemotherapy, Treated with Lower Doses of Chemotherapy Females, high risk of Radiation-Induced Secondary Malignancies Less prone to Chemotherapy-Induced Gonadal Damage Treated with More Intensive Chemotherapy without Radiation when Feasible. Bhatia S, et al.. Journal of Clinical Oncology. 2003; 21,4386

Effect of Radiation on Uterus Radiation Therapy in Girls may Cause Uterine Damage That leads to Pregnancy Complications such as: Miscarriage, Preterm Labor, Low Birth Weight

Gonadoprotective Measures No Effective Gonadoprotective Drugs are so far Available for use in Humans. Limiting radiation exposure by shielding or removing the testes from the radiation field should be implemented whenever possible

Endocrine Status Prepubertal Age

Pubertal Girls Aspiration In- vitro Fertilization Mature Oocyte Cryopreservation

Fertility Preservation in Children Cryopreservation of Embryos Most Eficient Technology Unmarried Vitrification of Mature Oocytes Both Methods Require Hormonal Stimulation Delay Urgent Treatment

Premenarchal - Females Aspiration of any Follicles Present Maturation in vitro Cryopreservation

Ovarian Tissue Cryopreservation Experimental 1997

Ovarian Tissue Slow Freezing Ovarian cortex is separated from the medulla Permeation of cryoprotective agents into the cells; to protect from freezing injuries Cryoprotective solution : dimethyl sulfoxide 1,2-propanediol sucrose and human serum albumin. Gradually Cooled Temperature reaches −140°C Plunged into liquid nitrogen at −196°C for storage

Rapid Freezing - Vitrification Ovarian cortical Fragments Immersed in a Highly Concentrated Cryoprotective Solution. Ovarian TIssue Plunged directly into Liquid Nitrogen For Storage

Histological examination revealed a higher percentage of degenerated follicles after cryopreservation and thawing. Conclusions Ovarian tissue cryopreservation and thawing impairs the viability of ovarian tissue in oncological patients opting for fertility preservation Journal of Assisted Reproduction and Genetics 2014:31, Efficacy of Ovarian Tissue Cryopreservation

Ovarian Tissue Preservation Denmark's registry, 18% of patients younger than 14 years of age ( 2011) Belgium - 59 girls under 16 years of age (2011) Hadassah, Jerusalem 15% under 15 years of age (2012)

Transplantation of Ovarian Tissue in Girls Orthotopic Location OVARY Transplantation can be performed Laparoscopy Laparotomy Heterotopic Location. Successful transplantation of ovarian tissue In girls has not yet been REPORTED

Fertility Preservation in Boys Malignant Conditions Leukemia Hodgkin's disease Non-Hodgkin's lymphoma Myelodysplastic syndromes Solid tumors Soft tissue sarcoma

Fertility Preservation in Prepubertal Boys Hematological disorders : thalassemia major, sickle cell disease, aplastic anemia, Fanconi anemia Primary Immuno-deficiencies Severe Autoimmune DIseases Unresponsive to immunosuppressive therapy: Juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, systemic sclerosis, immune cytopenias Enzyme Deficiency Disease: Hurler's syndrome *Risk of testicular degeneration Klinefelter syndrome

. Postpubertal Boys, Cryopreservation of mature spermatozoa is an ideal option. Semen may be obtained through: Masturbation Assistance of Penile or Rectal Stimulation Testicular Sperm Extraction Epididymal Aspiration Normal Mature Spermatozoa Survive Cryopreservation and Thawing very Well May be used in the future for Intrauterine Insemination In vitro Insemination.

Spermatogenesis

Fertility Preservation in Prepubertal Boys Animal data Healthy offsprings have been obtained after Transplantation of Frozen Testicular Cell Suspensions or Tissue Pieces. In Humans None of the fertility restoration options of Frozen Tissue Cell suspension Transplantation, Tissue grafting IVM Have proved Efficient and safe in humans as yet.

Spermatogenesis The Prepubertal Testis does not Complete Spermatogenesis Cytotoxic Treatment Given to Prepubertal Boys Afects Fertility,

Fertility Preservation in Prepubertal Boys Animal data Healthy ofsprings have been obtained after Transplantation of Frozen Testicular Cell Suspensions or Tissue Pieces.

Fertility Preservation in Prepubertal Boys In Humans None of the fertility restoration options of Transplantation, : Frozen Testicular Tissue Cell suspension Have Proved Efficient and Safe in Humans as Yet.

Prepubertal Boys Testicular-Tissue Harvesting and Cryo-preservation. An experimental process Its success relies not only on The Survival of the Tissue but also on its ability to graft After Reimplantation To restart the Cellular Processes Needed to Generate Mature Spermatogonia.

Fertility Preservation in Prepubertal Boys Fertility in Adult Life may be Severely Impaired by Gonadotoxic Therapies. For Young Boys who do not Yet Produce Spermatozoa, Cryopreservation of Immature Testicular Tissue (ITT) is an Option to Preserve their Fertility, Still Experimental

The ethics and legalities of medical treatment of children have always been an area of active discussion Due to ongoing Cognitive Physical Development in childhood Family well-being,.

Primary Physician Duty is to Provide Counseling to Children and their Families Regarding : The Risks of their Cancer Treatment of their Cancer Treatment Regarding Future Fertility Options for Fertility Preservation. Counseling to Children of all Ages, Should be done in a manner appropriate to both Age and Sexual Maturity

Ethical Issues of Fertility-Preservation Options Must be Considered on an Individual Basis Cancer diagnosis Recommended Treatment Prognosis Gonadotoxicity of Treatment, Length of Delay Fertility Preservation, Benefit Harm The Age and Desires of the Child Input of the Child ’ s Family.

Ethical Issues The Weighing of Harms and Benefits Is Extremely Difficult Because there are Inadequate Data on which to base an Individual Case

Ethical Issues Harms Delay of Treatment Hormonal Manipulations that Worsen Cancer Outcomes Reintroduction of Cancer Cells with Gonadal-tissue Following Reimplantation Risks of Surgical Interventions, Providing False Hope.

Ethical Issues Concerns about the Procreation of Cancer Survivals Decreased Life Expectancy Risk of Early Death in Adulthood Risk of Chronic Diseases ETHICALY ?

Fertility Preservation in Children Up to 20% of Children will be not cured of their Primary Cancers Part of 80% of Survivors Premature Death Ongoing Chronic Disease Precludes Future Use of any Cryopreserved Tissues or Gametes

Posthumous Reproduction Fertility Preservation in Children Conceiving a Child or implanting an Embryo Shortly Before or anytime After the Death of One or More of Its Parents Bethany Spielman, In Ethical Dilemmas in ART – ED.J Schenker Ben-Shoshan A and J.Schenker Hum Reprod May;13(5):

Parents may have the Legal Authority to Decide on the Disposition of Cryopreserved Tissue or Gametes To Assuage their Grief over their Loss To Experience Grandparenthood ART Practice Posthumous Reproduction

Two-Step Consent ISRAEL Cryopreservation Implantation

Warsaw-