ONKOFERTİLİTEDE GÜNCEL UYGULAMALAR. Dr. Bülent URMAN Koç Üniversitesi Tıp Fakültesi Amerikan Hastanesi

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1 ONKOFERTİLİTEDE GÜNCEL UYGULAMALAR Dr. Bülent URMAN Koç Üniversitesi Tıp Fakültesi Amerikan Hastanesi

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3 Oktem and Urman et al Oncologist 2018

4 Chemotherapy drugs exerts cytotoxic effects systematically and therefore, can damage the ovaries, leading to infertility, premature ovarian failure, and to lesser extent spontaneous abortions. They have very limited or no deleterious effects on the uterus that can be recognized clinically.

5 Kemoterapinin Over üzerine etkisi 2. Primordial foliküller 3. Büyüyen foliküller 1. Damarlar 3 dk içinde kan akımında azalma 2 saat içinde ölçülebilen DNA hasarı 4. Stroma Acute reduction in ovarian blood volume and narrowing of the small vessels Stromal fibrosis Blood vessel obstruction causes localized ischemia damage causing the loss of primordial follicles in that area Roti Roti EC, Plos One, 2012

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7 CYCLOPHOSPHOMIDE CONTROL Apoptotic death of oocytes and granulosa cells in human ovarian xenografts after exposure to cyclophosphamide Oktem et al 2007 Cancer Research

8 By contrast, radiation is detrimental to both the ovaries and uterus, thereby causing a greater magnitude of adverse effect on the female reproductive function. These include infertility, premature ovarian failure, miscarriage, fetal growth restrictions, perinatal deaths, preterm births, delivery of small for gestational age infants, preeclampsia and abnormal placentation

9 Radyoterapi ve Gondadotoksisite Radyoterapi protokolü Dozu Yaş grubu Gonadotoksi site Tüm vücut ışınlanması (Kemik iliği Yüksek transplantasyonu ya da kök hücre nakli için ) Pelvik ya da tüm abdomen ışınlanması 6 Gy Erişkin Yüksek Pelvik ya da tüm abdomen ışınlanması 10 Gy Postpubertal kızlar Yüksek Pelvik ya da tüm abdomen ışınlanması 15 Gy Prepubertal kızlar Yüksek Pelvik ya da tüm abdomen ışınlanması 5-10 Gy Postpubertal kızlar Orta Pelvik ya da tüm abdomen ışınlanması Gy Prepubertal kızlar Orta Kraniospinal radyoterapi 25 Gy Orta

10 Kanser tedavisi ve over fonksiyonları KEMOTERAPİ ve RADYOTERAPI Akut over yetmezliği- Amenorrhea Azalmış over rezervi-fertilitenin kaybı Prematür over yetmezliği & menopoz Aneuploidi artışı düşük oranında artış RADYOTERAPİ Düşük riskinde artma İntrauterin büyüme geriliği Düşük doğum ağırlıklı fetüs Erken doğum riskinde artma Plasenta anomalilerinde artma Yen&Jaffe reproductive endocrinology-7th edition

11 Determinants of ovarian toxicity AGE Younger patients have higher ovarian reserve (more follicles in their ovaries), therefore they are more likely to have some residual ovarian function after cancer therapy AGE 18 AGE 35 OVARIAN RESERVE CHEMO CUMULATIVE DOSE RADIATION

12 STRATEGIES TO PRESERVE FERTILITY DRUGS OVARIAN TISSUE FREEZING OOCYTE/EMBRYO FREEZING OVARIAN TRANSPOSITION EXPERIMENTAL EXPERIMENTAL ESTABLISHED ESTABLISHED? Lack of a proven mechanism of action Inconsistent RCT results Untested in human Sixty live birth to date All pregnancies from orthotopic sites Requires young patients with good ovarian reserve Does not reverse menopause Time honored method CPR 60% per FET Does not reserve menopause May not prevent POF Uterine exposure to RT

13 Oosit dondurma ICSI Kriyoprotektanlardaki gelişmeler Vitrifikasyon ASRM 2013: oosit cryo deneysel değil

14 Biological efficiency of IVF-oocyte to baby From Patrizio and Sakkas. Fertil Steril 2009

15 10 çalışma 1805 hasta

16 Yaş, çözülen oosit, transfer edilen embriyo başına canlı doğum oranları Slow Freezing Oocytes Thawed Oocytes Injected Embryos transferred Age Vitrification Oocytes Thawed Oocytes Injected Embryos transferred Age Cil AP, Fertil Steril 2013

17 Efficiency of oocyte vitrification for fertility preservation From Cobo et al. Fertil Steril 2016

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19 Predicting the likelihood of live birth for elective oocyte cryopreservation: a counseling tool for physicians and patients. Goldman et al. Hum Reprod 2017

20 Başarı ve Güvenilirlik İmplantasyon, abort ve canlı doğum oranları embriyo transferine göre benzer >6000 canlı doğum Konjenital anomaliler, major ve minör malformasyonda artış yok Cobo A, Fertil Steril 2014 Noyes N, Reprod Biomed Online, 2009

21 Elective FP vs Onco FP Cobo et al Human Reprod 2018

22 Stimulasyon protokolleri GnRH antagonistleri Zaman OHSS riski düşük Aromataz inhibitorleri Estrojen sensitif kanserlerde güvenli Random Start Protokoller COS 1-2 gün uzar Kullanılan Gn dozu daha fazla Embriyo kalitesi ve gebelik oranlarında fark yok DuoStim FertiPROTEKT network, Arc Gynecol Obstet,2011 Oktay K, J Clin Oncol, 2015 Kim J, J Clin Endocrinol Metab Boots CE, J Assist Reprod Genet, 2016 FertiPROTEKT study group, Eur J Obstet Gynecol Reprod Biol Letourneau JM, Hum Reprod, 2017 Turan V, Fertil Steril, 2013

23 34 y, G1 5 haftalık gebe, ER +, PR+, HER-2 negatif, infiltran intraductal meme kanseri Terminasyondan 5 gün sonra RANDOM START stimülasyon (beta HCG: 118) 29 oosit, 17 fertilize, 10 blastosist cryo

24 OVARIAN TISSUE FREEZING Transplantation Thawing Freezing Heterotopic sites Arm Abdomen Orthotopic sites Ovary Pelvic side wall

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27 Ovarian tissue cryopreservation Requires young patients < 35 Indicated for patients who Have no time or contraindication for ovarian stimulation for oocyte and embryo freezing. Only option for pediatric and adolescent cancer patients 134 live births reported to date Considered still experimental

28 Riskler Transplantasyon sonrası folikül kaybı Transplante dokuda residüel malign hücrelerin varlığı ve kanser nüksü

29 Risk of metastasis to the ovay Over metastazı riski olan kanserler Düşük risk (<1%) Orta risk (1%-11%) Yüksek risk (>11%) Oktem., Sonmezer., Oktay.,Textbook of Assisted Reproductive Technologies, 2005

30 Transplant ömrü Canlı doğumlar Gook DA, Best Prac Research Clın Obstet Gynecaol,

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32 GnRH analogları

33 GnRHa-tartışmalı

34 RCT vs Cohort Type of malignancy

35 1 HUMAN OVARIAN TISSUE CULTURE 2 HUMAN GRANULOSA CELL CULTURE Immortalized proliferating granulosa cells (COV434) Luteal nonproliferating granulosa cells (HLGC) CHEMOTHERAPY ±GNRHA CHEMOTHERAPY ±GNRHA CHEMOTHERAPY ±GNRHA REAL TIME MONITORIZATION and QUANTIFICATION OF CYTOTOXICITY With XCELLIGENCE SYSTEM ESTRADIOL AND PROGESTERONE PRODUCTION ASSESSMENT OF OVARIAN TOXICITY Follicle Counts AMH Progesterone Estradiol APOPTOSIS AND CELL VIABILITY MARKERS

36 STRATEGIES TO PRESERVE FERTILITY DRUGS OVARIAN TISSUE FREEZING OOCYTE/EMBRYO FREEZING OVARIAN TRANSPOSITION EXPERIMENTAL EXPERIMENTAL ESTABLISHED ESTABLISHED? Lack of a proven mechanism of action Inconsistent RCT results Untested in human Sixty live birth to date All pregnancies from orthotopic sites Requires young patients with good ovarian reserve Does not reverse menopause Time honored method CPR 60% per FET Does not reserve menopause May not prevent POF Uterine exposure to RT