Oocyte Cryopreservation And Other Reproductive Options For Cancer Patients Human Oocyte Nicole Noyes M.D. Professor Co-Director of Oocyte Cryopreservation Program NYU Fertility Center New York University School of Medicine
Learning Objectives • At the conclusion of this session, participants should: – Be aware of the fertility preservation options available for patients diagnosed with malignancies (as well as other illnesses whose treatment will result in iatrogenic ovarian compromise) – Appreciate the complexity that may exist and the communication necessary to successfully include fertility preservation into a patient’s cancer care
Landscape Has Cancer: BIRTH AGE: Changed Improved Dx/Rx → Maternal Age @ 1 st Birth: Increased Survival: 77% Dx’d @ <45 y >25 y US; Globally up to 31 Live ≥5 y All Time High Oncofertility Improved ART & Communication: Egg Freezing & FP Options Email and PDAs
Percent of malignancies diagnosed <45 y: 40% cervical 13% breast 12% ovarian 8% endometrial * U.S. Female Cancer Incidence/Mortality by Site - 2010 American Cancer Society 2011
Probability of Menopause During 1 st Year after Breast Cancer Diagnosis Goldhirsch. Ann Oncol 1990;1:183 Bianco. Br J Cancer 1991;63:799 Cobleigh.Proc Am Soc Clin Oncol 1995;14:A158 Bines. J Clin Oncol 1996;14:1718 Del Mastro. Br Cancer Res Treat 1997;43:183 Meirow. Hum Reprod Update 2001;7:535 Goodwin, P. J. et al. J Clin Oncol 1999;17:2365. Partridge. Proc Am Soc Clin Oncol 2005;25:687 Partridge. J Cancer 2007;43:1646
When are Women Having Babies? U.S. Census Data Women 65 million of reproductive age Birthrate Decline teenage years 20-29 yrs 30-34 yrs Birthrate Rise 35-39 yrs 40-44 yrs (highest since 1969) OECD.org Given the choice, both men and women prefer Reproductive Autonomy
Human Oogenesis 20 weeks gestation: 6-7 x 10 6 oocytes No further germ cell proliferation Progressive atresia begins Birth: 1-2 x 10 6 oocytes Puberty: 300,000 (15%) oocytes Monthly cohort of follicles initiate growth and development one “ovulates” others become atretic Age 30: 240,000 (~12%) oocytes Age 40: 60,000 (~3%) oocytes accelerated atresia Accelerated atresia coincides with decrease quantity and quality of oocytes
Considerations • Age (suspected ovarian reserve) • Type of cancer and treatment planned • Presence of partner • Willingness to use donor gametes • Available time before cancer treatment • Health of the patient • More than one option may be possible for a given patient
2006 ASCO Guideline Summary As part of informed consent prior to therapy, oncologists should address the possibility of infertility with patients as early in treatment planning as possible 1 FP important, if not necessary, consideration when planning cancer treatment in reproductive-age patients 1 Lee SJ, Schover LR, et al., Journal of Clinical Oncology, 2006
Fertility Preservation Options
Assisted Reproductive FP Techniques Options Freeze Mature Oocytes Freeze Embryos In Vitro Maturation Freeze Mature Oocytes Sperm Mature Oocyte Collect Immature Eggs (Germinal Vesicle & MI) Freeze Tissue
1. Embryo Banking Standard of Care • Readily available technology in most developed countries • Good option if male partner committed to co- parenting exists • Disposition issues - Cancer associated with increased morbidity and mortality limiting ultimate usage
Embryo Banking Supernumerary Embryo Data Live Birth Rate: ~33% FET Age < 35 35-37 38-40 41-42 Fresh 48% 38% 28% 17% Live birth/ET Thawed 36% 31% 26% 22% Live birth/ET Average # embryos transferred: 1.5 per fresh and 2 per FET Data from 2009 SART Statistics (90,310 Fresh non-donor cycles; 21,646 Thawed non-donor cycles )
2. Oocyte Banking Considered experimental • Rapidly evolving FP technology • Theoretically, the optimum alternative for women not in a committed male-female relationship • Less disposition issues
Oocyte Cryopreservation Despite experimental label Occurring worldwide Survey of USA IVF centers: • 442 centers contacted: 282 (64%) responded over 49 states • 51% of programs currently offer oocyte cryopreservation • 337 live births from 857 thaw cycles: 39.3% live birth rate ~Similar to embryo thawing success Rudick, Opper, Paulson, Bendikson, Chung. Fertil Steril 2010 Epub ahead of print DOI: 10.1016/j.fertnstert.2010.04.079
Oocyte Cryopreservation • First human pregnancy was reported in 1986 • Early results disappointing – Techniques not reproducible – Low oocyte survival, fertilization and pregnancy rates after IVF with thawed oocytes • Oocytes difficult to freeze because of ice crystal formation – Large cell size (100 micrometers) – High water content – Chromosomal arrangement (meiotic spindle)
Spindle / Chromosomes - Effect of Cooling Human oocyte cooled to 0 ° C. Arrows indicate precocious segregation of single chromatids. Careful dehydration to avoid ice-crystal formation Zenzes 2001 Fertil Steril 75; 769
Female Fertility Preservation Oocyte Cryopreservation Advances
Human Oocyte Cryopreservation Literature-Reported Live Births n = 609 Births 9 yrs Slow Freeze (n = 308) Vitrification (n = 289) Both (n = 12)
Safety: Oocyte Preservation Cumulative Data No increase in birth anomalies
Oocyte Cryopreservation Donor Oocyte Cycles 89% 88% 68% 16/20 = 80% Currently >200 babies born 15 ♀ delivered 26 babies Nagy et al . Fertil Steril 2009;92:520
Oocyte Cryopreservation Donor Oocyte Cycles RCT - vitrified vs. fresh Vitrified Oocytes Fresh Oocytes n = 295 n = 289 Mean age of egg donor (y) 26.7 26.6 Estradiol day hCG (pg/ml) 2879 2892 Mean no. oocytes 10.3 11.2 Fertilization % 74.2 73.3 Mean no. embryos transferred 1.7 1.7 Implantation rate % 39.9 40.9 Clinical pregnancy rate/transfer % 55.4 55.6 • No significant difference in any parameter Now have >600 liveborn babies Cobo et al. Human Reprod 2010;25:2239
Oocyte Cryopreservation Donor Oocyte – Fresh vs. Vit 77 transfers – oocytes divided 2 (n=31) or 3 (n=5)
Oocyte Cryopreservation Randomized Sibling Oocyte Trial
Oocyte Cryopreservation Donor and Autologous Thaw Cycles Noyes et al. Fertil Steril 2011;94:2078-2082
NYU Fertility Center Thaw Data 44 cycles – 20 women delivered 28 Babies (12 singleton, 8 twin) 45% delivered rate Oocyte Autologous Autologous Autologo Recipient <35 y 35-40 y us (n = 15) (n = 18) (n = 9) >41 y (n = 2) 28 32 38 43 Mean Age @ Oocyte Harvest 11* 20 14 9 Mean # Oocytes 10 16 12 9 MII Oocytes Pregnancies 11 (73%) 9 (50%) 4 (44%) 0 Miscarriage 2 1 1 0 Delivered 0 9 (60%) 8 (44%) 3 (33%) Single/Twin 4 singleton, 5 twin 5 singleton, 3 twin 3 singleton 0 *no. assigned to recipient ½ slow, ½ vitrification NYU, unpublished data
NYU Fertility Center Update Medical Oocyte Freeze Cycles 9/2005 - 9/2010: n = 90 P OC - Cancer OC with thaw – Non-Cancer Rapid communication (n = 50) (n = 32) with pt and between oncologist and RE essential Age (y) 31 ± 1 32 ± 1 0.9 No. oocytes retrieved 19 ± 2 22 ± 2 0.2 No. mature oocytes 15 ± 2 14 ± 2 0.9 cryopreserved 38% GYN, 30% breast, 19% hematologic, 13% other NYU, unpublished data Noyes et al. 1 st 50 cycles. JARG 2010;27:495-499
NYU News 3 transfers in cancer survivors to date First pregnancy one week ago ßhCG level today (day 33): 750 IU/L Breast cancer survivor Frozen at age 40; thawed at 43
Egg/Embryo Freezing The process takes ~2 Weeks Estradiol rise hCG or lupron ovulation Egg retrieval/evaluation OCP +/- trigger Egg freeze GnRH If embryos: insemination antagonist and/or Letrozole Zygote freeze Gonadotropin SQ 2 11 13 14 21 Menstrual Cycle Day
3. In Vitro Maturation (IVM) of Immature Oocytes Considered experimental • Retrieval and banking of immature oocytes after no or limited gonadotropin stimulation or hCG • Advantages – Shorter duration – Potentially less cost – Lower risk of ovarian hyperstimulation syndome (OHSS) • Disadvantages – Lower success rates – Limited outcome data
IVM With and without priming No Priming hCG alone FSH alone FSH + hCG 10,000 IU 150IU/day x 3d (n = 100) (n = 100) (n = 100) (n = 100) Age (y) 33.1 33.1 33.6 33.2 # Oocytes 5.3 5.3 4.8 5.4 MII at retrieval 0 5.7% 0 20.3% Fertilization 78% 72% 73% 73% Clin Preg Rate/cycle 11% 5% 13% 26% Clin Preg Rate/ET 15.3% 7.6% 17.3% 29.9% Implantatioin Rate 9.2% 4% 10.6% 16.4% FSH started cycle day 3, IVM x 30 hours, ICSI Currently 156 babies born. Mean # transferred = 1.8, No ET in 21% Not in cancer pts; more PCO Fadini et al. Reprod Biomed Online 2009;19:343
IVM and tissue cryopreservation in children and adolescents No births to date
4. Ovarian Tissue Banking Considered experimental • No ovarian stimulation, minimal delay in treatment, no partner needed, only option in prepubertal girls • Requires surgical removal of ovarian tissue – Autologous pelvic transplantation – human births – Maturation in vitro – no human births • Exciting technology but few successes and many unanswered questions
Laparoscopic Removal of Cortical Tissue
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