Fertilità e programma di crioconservazione

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Niccolina Baldi
8 anni fa
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1 Fertilità e programma di crioconservazione Enrico Vizza Responsabile S.C. Ginecologia Oncologica Istituto Nazionale Tumori Regina Elena Roma

2 Advances in oncological diagnosis and treatments have resulted in a marked improvement in the survival of children and young adults with cancer Distribuzione dei tumori femminili in età riproduttiva Tumori femminili Jemal et al 2003 % in donne < 40 anni 8% Oktay e Yih 2002 Sopravvissuti tumori infantili (1/1000) Stima sopravvissuti al Simon /250 pz Blejer 1990

riproduttiva Tumori femminili 650000 Jemal et al 2003 % in donne < 40 anni 8% Oktay e Yih 2002

3 Neoplasie prepuberali Leucemia linfatica acuta, linfoma di Hodgkin, neuroblastoma, linfoma non-hodgkin, tumore di Wilms, sarcoma di Edwing, osteosarcoma della pelvi e rabdomiosarcoma. ALL è la neoplasia più comune in età pediatrica. Sopravvivenza a 5 anni è 80-86%.

sarcoma di Edwing, osteosarcoma della pelvi e rabdomiosarcoma.

4 Incidenza delle neoplasie Ginecologiche per età % anni > 46 anni

5 Carcinoma mammario Carcinoma della portio Carcinoma ovarico E la neoplasia più comune della donna in età riproduttiva 15% casi <40 aa di età donne/anno nel mondo 50% prima dei 35 aa 3-7% < 40 aa nei primi stadi 14% < 40 negli stadi avanzati Carcinoma endometriale 7-8 % nelle donne <35 aa I stadio

donne/anno nel mondo 50% prima dei 35 aa 3-7% < 40 aa nei primi stadi 14% <

6 Premature ovarian failure (POF) is one of the most common long-term adverse effects affecting premenopausal patients treated with alkylating agents. Rischio alto Rischio intermedio Rischio basso Ciclofosfamide Cisplatino Mathotrexate Clorambucil Adriamicina 5-fluorouracile Melfalan Vincristina Busalfan Actinomicina C Procarbazina Bleomicina Mostarde azotate

Rischio alto Rischio intermedio Rischio basso Ciclofosfamide Cisplatino Mathotrexate

7 Premature ovarian failure (POF) is one of the most common long-term adverse effects affecting premenopausal patients treated with alkylating agents. La dose mediana di ciclofosfamide che Rischio alto Rischio può indurre intermedio Rischio basso Ciclofosfamide Cisplatino amenorrea in donne Mathotrexate < 40 anni 5,2g; 9,3g Clorambucil Adriamicina in donne di 30 anni 5-fluorouracile Melfalan e 20g in donne < a 30 anni Vincristina Busalfan Procarbazina Mostarde azotate Actinomicina C Bleomicina

La dose mediana di ciclofosfamide che Rischio alto Rischio può indurre intermedio Rischio basso Ciclofosfamide Cisplatino

8 Premature ovarian failure: 68% women treated with alkylating agents for breast cancer 38-57% women treated for lymphoma 90% women treated with conditioning regimen for bone marrow transplantation

9 Amenorrea permanente dopo chemioterapia (6 cicli di CMF per cancro alla mammella) Mattle et al 2005

10 Radiotherapy is also recognized to cause destruction of the follicular pool, with a Lethal Dose 50 (LD50) of human oocyte, 2 Gy. (Wallace et al., 2003) The effective sterilizing dose at which ovarian failure occurs immediately after treatment in almost all the patients is estimated at 20 Gy, when pelvic radiotherapy doses for intraabdominal tumour, including gynaecological cancer, ranged from 25 to 50 Gy. (Meirow and Nugent, 2001; Chemoradiotherapy for cervical cancer Meta-Analysis Collaboration, 2008; Wo and Viswanathan, 2009)

, 2003) The effective sterilizing dose at which ovarian failure occurs immediately after treatment in almost all the patients is

11 The chance of spontaneus pregnancy in women treated after 25 years of age has been estimated to be only 5%. (Lobo, 2005) For these women not-sterilized by radiaction or chemotherapy, there may be an increased risk of complication during pregnancy such as early pregnancy loss, premature labor and low birth weight (Oktay et al 2004)

(Lobo, 2005) For these women not-sterilized by radiaction or chemotherapy, there

12 Different strategies for fertility preservation Established Emerging Revolutionary Gonadal shielding Ovarian suppression Apoptotic inhibitors Ovarian trasposition Oocytes cryopreservation Xenografting cryopreserved ovarian tissue Embryo cryobanking Donor oocytes Ovarian tissue cryopreservation Reconstructed oocytes

Ovarian trasposition Oocytes cryopreservation Xenografting cryopreserved

13 Options to preserve/restore fertility Reduce the gonadotoxicity Oocytes donation Cryopreservation of oocytes, ovarian tissue, embryo.

14 Options to preserve/restore fertility Ovarian transposition Adaptation of chemotherapy regimen Pharmacology: GnRh agonist Apoptotic Inibitors Sphingosine -1-phosphate 88,6 % retained ovarian function in women under age % of pregnancies were spontaneus with 75% occurring without reposition

Sphingosine -1-phosphate 88,6 % retained ovarian function in women under

15 Options to preserve/restore fertility According to the Ethics Committee of the American Society for Reproductive Medicine (2005), the only established method of fertility preservation is embryo cryopreservation. Survival rates per thawed embryo range However, this option requires the patient from to 35% be of to pubertal 90% and age, implantation have a partner rates or use donor sperm, and be able to undergo a cycle from 8% of ovarian to 30%. stimulation, which is not possible when chemotherapy The has pregnancy to be initiated rate is immediately 28% with or when stimulation is contraindicated according cryopreserved to the type embryos of cancer versus 34% with fresh embryos.

Survival rates per thawed embryo range However, this option requires the patient from to 35% be of to pubertal 90% and age, implantation have a partner rates or use donor

16 Options to preserve/restore fertility Limitation of embryo cryopreservation Controlled ovarian hyperstimulation and oocytes retrieval -2/3 weeks before onset of chemotherapy Partner or donor sperm Supraphysiologic estradiol levels from controlled ovarian hyperstimulation in patient with breast cancer

onset of chemotherapy Partner or donor sperm Supraphysiologic estradiol

17 Options to preserve/restore fertility Cryopreservation of oocytes can be performed in single women who are able to undergo a stimulation cycle, although the effectiveness of this technique is still low, with pregnancy and delivery rates ranging from 1 to 5% per frozen oocyte

stimulation cycle, although the effectiveness of this technique is

18 Options to preserve/restore fertility Fattori che influenzano la sopravvivenza ovocitaria Fattori biofisici Crioprotettore, congelamento/ scongelamento. Fattori morfologici Maturità,qualità e dimensioni, presenza di cumulo ooforo.

Crioprotettore, congelamento/ scongelamento.

19 Options to preserve/restore fertility There have only been 2 live births with IVF using in vitro maturation of immature oocytes (IVM) and oocyte cryopreservation. Georgescu E.S. et al 2008 It has also been suggested that IVM and oocyte vitrification may be performed with oocytes aspirated from antral follicles of ovarian tissue removed for cryopreservation Huang J.Y. Et al 2008

et al 2008 It has also been suggested that IVM and oocyte vitrification may be performed with

20 Options to preserve/restore fertility Cryopreservation of ovarian tissue is the only option available for prepuberal girls, and for woman who cannot delay the start of chemotherapy

21 Options to preserve/restore fertility It allows the storage of a large number of primordial and primary follicles It performed at any time of the menstrual cycle It is the only available option to preserve fertility in children

22 Inclusion criteria for ovarian tissue cryopreservation and trasplantation procedures

23 Indications for ovarian tissue cryopreservation Demeestere I. 2009

24 Ovarian tissue, removed by laparoscopic approach, can be frozen using two different approaches: as fragments of ovarian cortex; as the entire ovary with its vascular pedicle; Frozen-thawed ovarian tissue can be transplanted either to an orthotopic site or heterothopic site.

27 Ovarian function occurs 4-6 months after tranplantation and remains for a few months to more than 5 years

28 Thirty cases of orthotopic reimplantation of cryopreserved ovarian tissue have so far been reported and seven live births have been achieved yielding a pregnancy rate of almost 25%. No baby has been born after heterotopic autotransplantation

29 Despite these encouraging results, some important concerns still limit the application of the procedure and its success. age of the patient at tissue collection, ischemic injury occurring during the time necessary for the revascularization of the transplanted tissue from the support vessels possibility of reintroducing metastatic cells within the implant Decrease in fertility rate after transplantation is actually directly correlated with follicular depletion induced by the ischemic process

30 Options to preserve/restore fertility POF confirmed before/after cancer treatment No ovarian tissue or gametes cryopreserved

31 Considerazioni Sarà possibile assicurare e garantire il diritto alla procreazione, la qualità dei trattamenti di riproduzione medicalmente assistita, a tutte le pazienti oncologiche in età riproduttiva? Quale ente /organo dovrà gestire la conservazione del tessuto ovarico? Fino a quale età sarà possibile effettuare il reimpianto del tessuto ovarico? Quale è la gestione del tessuto ovarico dopo il decesso del donatore?

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