Disclosure. Fertility after Childhood Cancer. Female Oncofertility. Learning Objectives

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1 Fertility after Childhood Cacer Possibilities for Improvig Success Sheila Pritchard BC Childre s Hospital Disclosure I have o coflict of iterest No commercial iterests Nothig to disclose Cofessio. I am ot: A edocriologist A urologist A gyecologist A reproductive medicie specialist Learig Objectives Female Ocofertility To review mechaisms that ca adversely affect fertility i survivors of childhood cacer To review methods of fertility predictio To review the curretly available ad potetial future techologies for fertility preservatio i this populatio Ovaria Fuctio To produce mature oocytes ad hormoes Females have a fiite umber of oocytes I early embryoic life several millio follicles. By puberty 180,000 are left Healthy females will have 450 cycles over 37.5 years Meopause occurs whe approximately 1000 follicles remai. But fertility is usually lost 10 years before Faddy, Huma Reproductio 1996; Johso, Nature 2004; Wallace, Cacer

2 Follicle Populatio i healthy females from coceptio to meopause Wallace ad Kelsey, Plo S Oe 2010 Faddy, Gosde Hum Reprod 1996 Adverse Effects Radiatio-Effects o the Ovary The Ovaries may be directly damaged by radiatio to the abdome, pelvis or craiospial axis Oocytes are sesitive with a LD 50 of < 2Gy. Causes a icrease i apoptosis of the existig oocytes Effect o fertility varies accordig to: Wallace et al, It J Radiat, Ocol Biol Phys 2005, 62(3) 738 Dose Number of follicles preset at the time of treatmet May develop: Acute ovaria failure More commoly - Premature meopause Saders, Blood, 1996; Wallace, Cli Ocol

3 Adverse Effects -Radiatio Effect o the Hypothalamic-Pituitary axis Adverse Effects Radiatio -Effect o the Uterus >24Gy to aterior pituitary Ofte causes goadotropi deficiecy Delayed puberty or abset meses <24Gy to Pituitary affects ihibitio of GRH Premature release of GRH ad premature puberty At risk for ovaria failure later i life At risk for pregacy loss Uterus may be damaged by doses >10 Gy Decreased uterie vasculature Decreased muscular elasticity Decreased growth ad positioal abormalities for fetus Cervical icompetece ad preterm birth Wallace, Cacer 2011 Bath, Br J Obst Gyaecol 1999 Adverse Effects Chemotherapy:Effects o the Ovary Calculatio of Alkylator Equivalecy No sigificat effect of chemotherapy o the Hypothalamus/pituitary Uterus The ovary is chemosesitive: Follicular apoptosis Vascular shut dow of ovaria cortical areas causig ischemia Alkylatig agets are the biggest culprits Ovaria Failure does ot usually happe immediately. Ca take moths to years Morse et al Pediatr blood cacer 2013 Aget dose mg/m 2 Cyclophosphamide Ifosphamide Procarbazie Chlorambucil BCNU CCNU Melphela Thiotepa Nitroge Mustard Busulpha Correctio factor

4 Risk to Fertility based o Calculated Alkylator equivalecy Predictio How ca we Moitor Ovaria Reserve? Mestrual History ad FSH ot very useful CTX equivalet mg/m 2 Male Female <4000 ulikely ulikely % 30% % 50% > % 80% These figures are very approximate with cofidece itervals varyig up to +/- 15% Gree DM Pediatr Blood Cacer 2014;61:53-67 (female data) Gree DM J Cli Ocol 2010;28:332-9 ( male data) Atral follicle cout is useful but labour itesive Ati Mulleria Hormoe Reflects total primordial follicle umbers Declies withi 5 years of meopause. Questioable reliability i <20 year olds Ca be moitored sequetially to give rough estimate of ovaria reserve. There are o methods to measure oocyte quality 24 Fertility Preservatio Fertility Preservatio GRH agoists Ovaria Shieldig prior to XRT Ovaria traspositio Ovaries moved from radiatio field to elsewhere i the abdome For patiets due to receive pelvic radiatio GRH agoists bid GRH receptors i aterior pituitary. Prologed activatio disrupts the GRH pulsatility which the dowregulates secretio. GRH agoists decrease vascularity i ovary thus decreasig chemo exposure Iitial trials were disappoitig but recet studies are more promisig* ad show beefit of GRHa i fertility preservatio i adult wome. Still cotroversial but seems to offer some protectio agaist cyclophosphamide iduced damage Ca also be used to suppress mestruatio durig chemotherapy *Hickma Am J Obstst ad gyecol Oct

5 Fertility Preservatio Fertility Preservatio Embryo cryopreservatio Well established, BUT Must be post pubertal Oocyte stimulatio ad retrieval takes 2 weeks Need a parter (or willig to use doated sperm) so ot suitable for most of our patiets Oocyte Cryopreservatio Vitrificatio ow allows successful freezig of ufertilized oocytes Successful, approx 10,000 live births BUT Must be post pubertal Oocyte stimulatio ad retrieval takes at least 2 weeks Expesive $5-10,000 per course Expesive $5-10,000 per course Success rate 18-25% per embryo but improvig Now cosider oocyte preservatio after treatmet if high risk of premature meopause Moitor AMH to determie timig Fertility Preservatio Re-implatatio of ovaria cortical strips Cryopreservatio of ovaria tissue Ovaria Cortical strips high cocetratio of primordial follicles Cryopreserved ad later re-implated But Still experimetal but OK for pre pubertal girls No eed for hormoal stimulatio so o delay to treatmet Retur of ovaria fuctio i patiets who are meopausal 130 pregacies reported 1 pregacy reported from prepubertal ovaria tissue trasplatatio Risk of damage to ovary ad ivasive proceedure Risk of trasplatig maligat tissue Doez 2017 NEJM Schmidt KT et al, Fertil Steril, 2011,;95:

6 Fertility Preservatio Experimetal Approaches Fertility Preservatio or Alterative I Vitro Maturatio of oocytes Still experimetal 1 birth reported i a adult cacer patiet. Ovaria tissue Allo Trasplat from a siblig boe marrow door Whole ovary cryopreservatio ad re-implatatio Aimal data oly Seshadri, Br J Cacer,2006; Doez, Hum Reprod 2011; Wallace, Cacer 2011 If ovaries OK but uterus damaged: Surrogate Mother Trasplated uterus if uterus damaged 8 babies bor i Swede after uterie trasplat, 1 i USA ( Lacet 2015, NYT ov 2017) If ovaries damaged but uterus OK Doated oocytes Pregacy Outcome Itervetios to be cosidered For those who do achieve pregacy Previous uterie radiatio - Moitor fetal growth Previous hypothalamus/pituitary radiatio Moitor hormoe status Previous chemotherapy No icrease i risk of pregacy loss or periatal problems No icrease i geetic defects Prior to start of treatmet Ovaria traspositio Oocyte cryopreservatio Ovaria tissue cryopreservatio Durig Treatmet GRH agoists After Completio of Treatmet Moitorig of ovaria reserve Oocyte cryopreservatio Sigorello et al J Cli Ocol 2012, Wither et al Am J Hum Geet (6), 1282 Geeral Cosideratio Risk of impaired fertility Health of the patiet Cost of all procedures Availability Expertise ad Iterest 6

7 Male Ocofertility Adverse Effects Radiatio -Effect o the testis Normal Testicular Fuctios To produce spermatazoa Spermatogoial stem cells Sertoli (urse) cells 3 billio sperm / moth, 100 per heart beat!! Sperm maturatio time =74 days To produce male hormoes Leydig cells- produce testosteroe Testicular radiatio For leukemic ifiltratio ( Gy) TBI (10-12 Gy) Spermatogeesis is very sesitive to radiatio 0.1Gy ca impair spermatogeesis >1.2Gy ca cause permaet azoospermia Effects are immediate May have some recovery over a few years Leydig cells are more resistat Dysfuctio > 20Gy i prepubertal boys >30Gy i mature males BUT- log term Leydig cell damage occurs ad testosteroe levels may decrease 20 years later Rowley MJ, radiatio research 1974, Shalet, J Edocriol, 1989 Adverse Effects - Radiatio Effect o the Hypothalamus/Pituitary Adverse Effects - Chemotherapy Effects o the Testis Low dose craial radiatio (<2400) less likely to cause precocious puberty i boys High dose craial radiatio (>2400cGy) Goadotropi deficiecy risk icreases with dose Treatmet testosteroe replacemet Leydig cells rarely affected ( high cumulative doses oly) Germial epithelium ( spermatogeesis) is very sesitive to chemotherapy Alkylatig agets are the mai culprits Effects are immediate No sigificat effects o hypothalamus/pituitary Wallace, It J Adrol,

8 Calculatio of Alkylator Equivalecy Risk to Fertility based o Calculated Alkylator equivalecy Aget dose mg/m 2 Cyclophosphamide Ifosphamide Procarbazie Chlorambucil BCNU CCNU Melphela Thiotepa Nitroge Mustard Busulpha Correctio factor CTX equivalet mg/m 2 Male Female <4000 ulikely ulikely % 30% % 50% > % 80% These figures are very approximate with cofidece itervals varyig up to +/- 15% Gree DM Pediatr Blood Cacer 2014;61:53-67 (female data) Gree DM J Cli Ocol 2010;28:332-9 ( male data) Fertility Predictio Ivestigatio of Testicular Fuctio Fertility Preservatio Assessmet of pubertal status Secodary sexual characteristics reflects Leydig cell fuctio Testicular size reflects spermatogeesis Testicular shieldig durig radiatio Sperm Bakig prior to startig treatmet Must be Taer 4-5 Measuremet of plasma hormoes FSH, LH, Testosteroe, Ihibi B High LH, Low testosteroe = Leydig cell dysfuctio High FSH, Low Ihibi B = Impaired spermatogeesis Seme aalysis = Gold stadard Sperm cocetratio, motility, morphology, volume, fructose level, ph, Roadblocks to Sperm bakig Patiet factors Uwell or embarrassed Time may eed to start treatmet immediately Poor sperm cout because uwell Family/ Caregiver Factors System Factors Access to cryopreservatio Facilities that are child/tee friedly Cost - $ for iitial bakig, $200 per year 8

9 Fertility Preservatio -Surgical methods Itervetios to Cosider Surgical sperm retrieval Small icisio i the scrotum ad extractio of sperm from the epididymis or testis Sperm ca be obtaied from Taer stage II boys Roadblocks to surgical sperm retrieval Orgaizatio- OR time, access to cryopreservatio Cost -$2000 Experimetal methods Testicular tissue cryopreservatio ad re-implatatio ( risk of trasplatig maligat cells) I vitro maturatio Success i rats ad primates so far No viable optios for pre pubertal boys Pre treatmet Sperm bakig Testicular aspirate Testicular biopsy? Post treatmet Seme aalysis for cousellig Sperm bakig oly if have risk of relapse If have adequate sperm cout at ed of therapy it is ot expected to decrease util late i life Log term moitorig of testosteroe levels if had radiatio Team Approach Fertility preservatio i childre ad adolescets requires a team approach Ocology team ( physicia, social worker, ursig, family) Fertility specialists Edocriology Urology Gyecology Ethics Admiistrators to facilitate procedures Family doctor ofte has to orgaize fertility referral later o Guidelies ad Protocols 9