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Hananel Holzer, MD Medical Director, MUHC Reproductive Center McGill University Health Center Director, REI Division, Dept. of Obstetrics & Gynecology.

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Presentation on theme: "Hananel Holzer, MD Medical Director, MUHC Reproductive Center McGill University Health Center Director, REI Division, Dept. of Obstetrics & Gynecology."— Presentation transcript:

1 Hananel Holzer, MD Medical Director, MUHC Reproductive Center McGill University Health Center Director, REI Division, Dept. of Obstetrics & Gynecology McGill University McGill University Health Centre

2 A comprehensive approach for fertility preservation

3 Fertility preservation 713,220 new cases of female cancer were diagnosed in 2009 in the U.S. (Jemal 2009)713,220 new cases of female cancer were diagnosed in 2009 in the U.S. (Jemal 2009) Childhood cancers 1%. 122 new cases per million children (Skinner 2006)Childhood cancers 1%. 122 new cases per million children (Skinner 2006) By 2010, one in 250 people will be a cancer survivor (Blatt 1999)By 2010, one in 250 people will be a cancer survivor (Blatt 1999) 80% of children and adolescents diagnosed with cancer become long-term survivors80% of children and adolescents diagnosed with cancer become long-term survivors One of long-term side-effects of cancer therapy is premature gonadal failure – infertilityOne of long-term side-effects of cancer therapy is premature gonadal failure – infertility

4 Ovarian reserve Females born with a finite pool of oocytes ( Zukerman 1951)Females born with a finite pool of oocytes ( Zukerman 1951) Challenged by Johnson, Tilly et al; 2004, 2005; Germ line stem cells

5 Ovarian reserve W. Hamish B. Wallace 2010

6 Ovarian reserve W. Hamish B. Wallace 2010

7 Ovarian reserve W. Hamish B. Wallace 2010

8 Destruction of growing follicles loss of primordial follicles ovarian atrophy Chemotherapy

9 Primordial Follicle Count Ovarian Reserve Early Menopause and Infertility

10 The effect of chemotherapy on the ovary is not all or none No. of surviving primordial follicles following exposure correlates inversely to dose of chemotherapy mg/kg Dose of Cyclophosphamide Number of PMFs (p = ) (Meirow et.al. Hum Reprod 1999)

11 Focal ovarian cortical fibrosis No follicles in zone of fibrosis Wedge shaped- corresponds to the blood supply (Meirow et al. Hum Reprod 2007) Cortical fibrosis

12 Apoptosis Vascular injury Cortical fibrosis Chemotherapy: Direct and indirect damage cortex medulla (Meirow et al. Hum Reprod 2007)

13 Loss of regulatory mechanisms Loss of local regulatory factors (AMH?)Loss of local regulatory factors (AMH?) Accelerated recruitment of primordial follicles.Accelerated recruitment of primordial follicles. Decreasing ovarian reserveDecreasing ovarian reserve

14 Chemotherapy Alkylating agents:Alkylating agents: Cyclophosphamide,ifosfamide, nitrosoureas, chlorambucil, melphalan, and BusulphanCyclophosphamide,ifosfamide, nitrosoureas, chlorambucil, melphalan, and Busulphan not cell-cycle specific, highest risk of ovarian failure.not cell-cycle specific, highest risk of ovarian failure. AntimetabolitesAntimetabolites methotrexate, bleomycin, 5-fluorouracil, actinomycin- D, mercaptopurine, vincristine)methotrexate, bleomycin, 5-fluorouracil, actinomycin- D, mercaptopurine, vincristine) impact the cells of the metabolically active ovarian follicles, are considered to be low risk for gonadal dysfunctionimpact the cells of the metabolically active ovarian follicles, are considered to be low risk for gonadal dysfunction Platin - intermediate riskPlatin - intermediate risk

15 chemotherapy Women >40 years have a 90% chance of amenorrhea subsequent to multi-agent chemotherapyWomen >40 years have a 90% chance of amenorrhea subsequent to multi-agent chemotherapy younger patients 20% - 90%.younger patients 20% - 90%. All patients exposed to chemotherapy might have a diminished ovarian reserveAll patients exposed to chemotherapy might have a diminished ovarian reserve significant predisposition for developing premature ovarian failure. Infertility > 35 years.significant predisposition for developing premature ovarian failure. Infertility > 35 years. The estimated probability of early menopause was at least 25% at age 30 years (Letourneau, Cancer 2011)The estimated probability of early menopause was at least 25% at age 30 years (Letourneau, Cancer 2011)

16 Radiotherapy Direct damage to ovaries Damage to hypothalamic-pituitary axis Dose dependent; total dose and fractionation schedule Age dependent; size of primordial follicle pool Radiation field dependent Could also affect uterine function (M/C, IUGR, Premature deliveries)

17 Radiotherapy for a given dose of radiation, the younger patients are, the later the onset of premature menopause. LD50 <2 Gy. the effective sterilising dose falls with increasing age effective sterilising doses are 20·3 Gy at birth, 18·4 Gy at 10 years, 16·5 Gy at 20 years, and 14·3 Gy at 30 years. model to reliably predict the age of ovarian failure after treatment with a known dose of radiotherapy. ( W Hamish B Wallace, Lancet 2005, International Journal of Radiation Oncology*Biology*Physics 2005)

18 Reproductive outcome In animal studies, the risks of M/C and of malformed fetuses after chemotherapy are high.In animal studies, the risks of M/C and of malformed fetuses after chemotherapy are high. In humans, no increases in fetal malformation or M/C after anticancer drug treatment.In humans, no increases in fetal malformation or M/C after anticancer drug treatment. No higher risk of genetic or chromosomal abnormalities in offspring from parents that had been cancer survivors (Winther JF 2004)No higher risk of genetic or chromosomal abnormalities in offspring from parents that had been cancer survivors (Winther JF 2004) if conception occurs more than a year after cessation of the treatmentif conception occurs more than a year after cessation of the treatment cancer treatment has mutagenic effects on the oocyte that are present in growing follicles and the risk of mutagenesis is related to the stage of oocyte development during exposure and the drug regime used. (Meirow 2005)cancer treatment has mutagenic effects on the oocyte that are present in growing follicles and the risk of mutagenesis is related to the stage of oocyte development during exposure and the drug regime used. (Meirow 2005)

19 Fertility preservation

20 Indications: Cancer patients before gonadotoxic treatment Other diseases before gonadotoxic treatment Young patients with Turner syndrome, Fragile X premutation (FMR 1), Galactosemia Women in mid-thirties without partner ?

21 Options for fertility preservation Should be tailored according to: Patients agePatients age Type of diseaseType of disease Spread of the diseaseSpread of the disease Planned treatmentPlanned treatment Time availableTime available Whether she has a partnerWhether she has a partner (Holzer Tan 2005)

22 Options for fertility preservation Ovarian protection: Ovarian shielding Ovarian transposition prior to local radiotherapy: – –reduces dose to 5-15% – –patients <40 – –Laparoscopy – –Location depends on the planned radiation. – –Does not protect against chemotherapy. (Tulandi 2004)

23 Options for fertility preservation GnRH agonist acts to protect gonads during chemotherapy by preferentially steering cells into less active cell cycle stage with decline in response to chemotherapeutic agents Simulating pre-puberty. Direct effect? Decreased perfusion? Young patients. (Blumenfeld 2007,Huser 2008)

24 Options for fertility preservation 3 meta-analyses were published:3 meta-analyses were published: GnRHa are effective in preserving ovarian function and in reducing amenorrhoea (Clowse 2009, Ben Aharon 2010)GnRHa are effective in preserving ovarian function and in reducing amenorrhoea (Clowse 2009, Ben Aharon 2010) only prospective randomized studies:only prospective randomized studies: odds ratio of 3.5 favouring the use of GnRHa.odds ratio of 3.5 favouring the use of GnRHa. Higher rates of resumption of menses and ovulationHigher rates of resumption of menses and ovulation No improvement of pregnancy rates (Bedaiwy 2010)No improvement of pregnancy rates (Bedaiwy 2010)

25 Options for fertility preservation Some evidence that GnRHa has a protective effect.Some evidence that GnRHa has a protective effect. the final conformation is still awaited.the final conformation is still awaited. GnRH antagnist – faster desensitization.GnRH antagnist – faster desensitization. Flare up effect; combined treatment? (Mardesik 2004 von Wolff 2011)Flare up effect; combined treatment? (Mardesik 2004 von Wolff 2011) The GnRHa could be used to induce ovulation in a stimulated cycle.The GnRHa could be used to induce ovulation in a stimulated cycle. Reduced tumour cell sensitivity to chemo in E+ cases ?Reduced tumour cell sensitivity to chemo in E+ cases ?

26 Options for fertility preservation Apoptosis inhibition: Ceramide – 2 nd messenger signals apoptosis Sphingosine 1 phosphate (S1P) ceramid antagonist Interesting and promising; still far from clinical implementation (Morita, Paris, Perez, Tilly et al 1999,2000, 2002)

27 Cryopreservation for fertility preservation Transplantation of whole intact ovary by vascular anastomosis Wang et al Nature 2002; Imhof et al 2006; Bedaiwy et al 2007 Huge technical challenge, perfusion of the cryoprotectant In theory, risk of cancer cell transmission

28 Options for fertility preservation: Cryopreservation of ovarian tissue Available for pre- and post-puberty patients Hundreds to thousands of primordial follicles may be preserved. No medical delay. No ovarian stimulation. Does not require a male partner At least 2 surgical procedures (+ IVF) Anesthesia- risks Theoretic risk of neoplastic cells in transplanted tissue – recurrence?

29 Risk of presence of neoplastic cells in the transplanted tissue Subclinical involvement of Hodgkins Lymphoma has not been identified in ovarian tissue (Seshadri Gook et al 2006)Subclinical involvement of Hodgkins Lymphoma has not been identified in ovarian tissue (Seshadri Gook et al 2006) detection of Hodgkin lymphoma within ovarian tissue taken at the time of harvest for cryopreservation. (Bittinger 2011)detection of Hodgkin lymphoma within ovarian tissue taken at the time of harvest for cryopreservation. (Bittinger 2011) 58 patients with hematological malignancies underwent ovarian tissue cryopreservation58 patients with hematological malignancies underwent ovarian tissue cryopreservation after thawing, markers to detect minimal residual disease usedafter thawing, markers to detect minimal residual disease used real-time RT-PCR positive in one patient with CML.real-time RT-PCR positive in one patient with CML. this alarming result avoided tissue transplantation (Meirow et al 2008)this alarming result avoided tissue transplantation (Meirow et al 2008) Positive markers of CML and AML in cryopresrved harvested ovarian tissue (Dolmans 2010)Positive markers of CML and AML in cryopresrved harvested ovarian tissue (Dolmans 2010)

30 Risk of presence of neoplastic cells in the transplanted tissue Other organ transplants: donor derived malignancy ( Kauffman 2002, Ison 2011 AM J Transplant)Other organ transplants: donor derived malignancy ( Kauffman 2002, Ison 2011 AM J Transplant) Extreme caution is warranted before we assume that we understand tumour biology well enough to estimate the risk of transmission of malignant cells in autotransplanted ovarian cortex.Extreme caution is warranted before we assume that we understand tumour biology well enough to estimate the risk of transmission of malignant cells in autotransplanted ovarian cortex. BRCA 1&2 carriers - potential of developing ovarian cancer (Colgan 2001)BRCA 1&2 carriers - potential of developing ovarian cancer (Colgan 2001) Prophylactic BSO, transplant ovarian fragments?Prophylactic BSO, transplant ovarian fragments?

31 Options for fertility preservation: Cryopreservation of ovarian tissue Loss of follicles during transplantation and initial ischemia. Absence of inhibitory mechanism? Longevity of the graft? 14 pregnancies and live births reported : Donnez, Meirow* Rosendahl* (6 pregnancies,3 live births, 2 women)/12 cases. Demeestere (OTx2) *IVF Bias due to selective reporting?

32 Options for fertility preservation: Cryopreservation of ovarian tissue Culture and IVM of primordial follicles: 2 step culture system: culture of tissue followed by isolation of follicles and culture. Or using 3D supportive matrix. Culturing to MII is the next chalange ( Abir et al. Histol. Histopatho 2006 Picton et al. Reproduction 2008, Tefler et al. Hum Rep. 2008, Woodruff 2009) Suspension of isolated primordial follicles (Dolmans et al 2008) Xenotransplantation: human ovarian tissue to SCID mice. Aberrant microtubule and chromatin patern. Transmission of pathogens, short life span ethical issues, and … ( Lucifero 2002, Kim 2001)

33 Embryo cryopreservation Integral part of IVF programs >25 years Success rates 30-50% per embryo transfer, depending on the age at the time of oocytes retrieval. Only well-established option of fertility preservation Post pubertal patients. Partner required Donor sperm?

34 1 st live birth 1986 (Chen et al) But: oocytes vulnerable to freezing process intracellular ice formation membrane rupture, abnormal cortical granule reaction, zona hardening, meiotic spindle and cytoskeleton damage : 5 live births No male partner: Oocyte cryopreservation

35 Using PROH/sucrose slow freezing protocol and introduction of ICSI improved pregnancy rates (Porcu et al 1997) Reported survival rates for mature oocytes (collected from stimulated ovaries) are 50-70% No male partner: Oocyte cryopreservation

36 Oocyte vitrification Cryoprotectants in high concentration used to induce glasslike state, cell then rapidly frozen avoiding formation of intracellular ice Kuleshova et al, 1999: survival rate 65%, PR/ET 21% Yoon et al, 2003: survival rate 69%, implantation rate 6.4%, PR/ET 21.4% Katayama et al, 2003: survival rate 94%, PR/ET 33%

37 Oocyte vitrification 165 live births (Chian et al ASRM 2007: McGill Reproductive Center in Canada, Instituto Mexicano de Infertilidad in Mexico and CECOLFES in Colombia) A few thousand babies Vitrification is emerging to be a better technique.

38 Embryo or oocyte cryopreservation after ovarian stimulation Pregnancies reported are result of fertilization of frozen/thawed oocytes collected after ovarian stimulation However: time interval needed for ovarian stimulation 2-6 weeks. Starting during menstruation Time may not be available for cancer patients Recent studies: stimulation luteal phase. (Von Wolff 2009, Sonmezer 2011) ovarian stimulation associated with high estrogen levels which may not be safe in cases of hormone sensitive tumors such as breast cancer Estrogens may have an indirect mitogenic effect on receptor negative cancers. (Gupta PB 2006)

39 Embryo or oocyte cryopreservation after ovarian stimulation Aromatase inhibitor + FSH: letrozole started 2 days before FSH administration, then given concomitantly, no increased risk of relapse (Oktay 2005, 2007, Azim 2008) Lower estradiol levels does not totally avoid stimulation Early follicular start of treatment. More studies are needed

40 Collection of immature oocytes from unstimulated ovaries Pincus, J Exp Med 1935; Edwards, Nature, 1965,1969. Cha et al,1991: Immature oocyte laparotomy for oocyte donation Trounson et al, 1994: IVM: vaginal collection of immature oocytes, for PCO related infertility

41

42

43 Mature oocytes at oocyte collection in IVM cycles 8mm 12mm 14mm

44 Vitrification of IVM oocytes? Could oocytes collected from unstimulated ovaries, matured in vitro, then vitrified survive thawing and be fertilized? Could transfer of these embryos result in a viable pregnancy ?

45 No. of patients20 Mean age30.7 ±3.7 No. of mature oocytes retrieved7 No. of immature oocytes retrieved295 Mean oocyte maturation rate (%) No. of oocytes vitrified and thawed215 No. of oocytes survived (mean % + SEM )148 ( ) No. of oocytes fertilized (mean % + SEM)96 ( ) No. of embryos transferred (median; range)64 (3.2; range 1 - 6) No. of implantations (mean % + SEM)5 ( ) No. of clinical pregnancies (%)4 (20.0) No. of live births (%)4 (20) Holzer et al ESHRE 2007 Vitrification of IVM oocytes

46 Conclusions Vitrification of in-vitro matured oocytes collected from unstimulated ovaries followed by later thawing and fertilization can result in successful pregnancies and live births

47 Conclusions Preliminary results 20 patients, all with PCO 20% pregnancy rate (vs. 35% in Fresh IVM ) Lower implantation rate (10.8% vs. 14.4%) Learning curve?

48 Conclusions Collection of immature oocytes from unstimulated ovaries followed by IVM and vitrification of mature oocytes could be offered to patients with hormone- sensitive disease and/or when there is not enough time to stimulate ovaries – –no risk of aggravating disease – –no theoretic risk of re-instituting metastatic malignant disease – –does not require same amount of time as that needed for ovarian stimulation, no need to wait for next cycle

49 When ovarian tissue is being harvested Additional strategy of fertility preservation combines ovarian tissue cryobanking with retrieval of immature oocytes from excised ovarian tissue, followed by in vitro maturation (IVM) and vitrification (Huang, Tulandi, Holzer, Tan, Chian Fertil Steril 2007) When surgery performed to remove ovarian tumor or for other therapeutic indications

50 Fertility preservation in prepubertal children Childhood and adolescence period of emotional and psychological instability; issues of sexuality, including fertility, are of particular importance Depletion of primordial oocytes after gonadotoxic treatment proportional to size of oocyte pool Younger patients have more oocytes; thus gonadal damage could seem to be less severe than in older patients

51 Fertility preservation in prepubertal children Global incidence of acute ovarian failure in childhood cancer survivors ranges from 6.3 to 12% (Bakker 2004) In Childhood Cancer Survivor Study ;the relative risk for survivors of ever being pregnant was 0.81 (Green DM 2009) Very few treatments benefit younger patients at risk of infertility after treatment

52 Fertility preservation in prepubertal children; Ovarian tissue cryobanking Primary method of fertility preservation for prepubertal girls One ovary removed from 47 patients aged y (median: 5) Ovarian tissue fragments frozen strong inverse correlation found between age and follicular density none of the cases had visible ovarian tumour components (Poirot 2007) 58 patients years, underwent ovarian tissue cryopreservation. 1 case of ovarian lymphoma infiltration (Jadoul 2010)

53 Fertility preservation in prepubertal children: Combined approach Unilateral oophorectomy: 19 patients aged 5-20 years (median 15 yrs.)Unilateral oophorectomy: 19 patients aged 5-20 years (median 15 yrs.) Antral follicles aspirated, average no. of oocytes: 9 (0-37)Antral follicles aspirated, average no. of oocytes: 9 (0-37) GV oocytes – IVMGV oocytes – IVM mature oocytes – frozenmature oocytes – frozen Ovarian tissue – cryopreserved in fragmentsOvarian tissue – cryopreserved in fragments (Revel 2008)

54 Fertility preservation in prepubertal children: Ovarian tissue cryobanking Reimplantation of ovaries cryopreserved before puberty not yet performed in either nonpubertal or pubertal recipients Animal models: puberty and fertility restored (Sauvat 2008) Removal of entire ovary, although strongly advocated by some, may not be recommended for pediatric patients in whom fertility outcome is often uncertain. How much? Based on the risk of the planned treatment and the ovarian volume.

55 Fertility preservation in pre- pubertal children Fertility preservation should now be considered in children facing cancer treatment with high risk of gonadal toxicity, including high-dose chemotherapy and bilateral irradiation of gonads at toxic doses Multidisciplinary team

56 McGill Fertility Preservation Center: Catchment Area Greater MontrealGreater Montreal QuebecQuebec Other Canadian provincesOther Canadian provinces USAUSA Trance AtlanticTrance Atlantic Physicians: Oncology, Haematology, Radiation Oncology, Surgery, Paediatrics.Physicians: Oncology, Haematology, Radiation Oncology, Surgery, Paediatrics. Nurses: nursing coordinators.Nurses: nursing coordinators. Non- medical professionals, self referralsNon- medical professionals, self referrals

57 Available and accessible: next day appointment policy.Available and accessible: next day appointment policy. Reciprocal: referring physician should be available, take part in planning.Reciprocal: referring physician should be available, take part in planning. Counsellor onsite or available via phone, Skype, webcamCounsellor onsite or available via phone, Skype, webcam On-going collaboration, individual casesOn-going collaboration, individual cases By-pass, current road blocks of the medical system.By-pass, current road blocks of the medical system. Medico legal issuesMedico legal issues Accessibility

58 Issues discussed with treating physician Treatment: drugs, dose.Treatment: drugs, dose. Time frame- coordinate treatments and tests.Time frame- coordinate treatments and tests. Survival?Survival? Risks of:Risks of: StimulationStimulation CollectionCollection Anaesthesia.Anaesthesia.

59 Long term follow up US (AFC)FSH AMHConsultationCounselling 2 nd collection Luteal collectionAdditional cycle Treatment Oocyte CPEmbryo CPOvarian tissue CPGnRH-aFollow up Nursing consultation Discuss and teach planned treatmentDraw blood testsFeedback to physician Consultation review of all options, tailored options GnRH analogDo nothing3rd partyOvarian tissueOocyte (IVF/IVM)Embryo (IVM/IVM) Appointment at the fertility preservation center History taking (Fellow)Ultrasound (AFC, cycle stage) Initial contact secretary InformationSchedule TREATINGPHYSCIANTREATINGPHYSCIAN COUNSELLINGCOUNSELLING

60 McGill Fertility Preservation Center 396 women with various malignancies underwent oocyte retrieval 184 underwent oocyte retrieval without ovarian stimulation followed by IVM : – –113 IVM cycles with vitrification of oocytes – –71 IVM cycles, matured oocytes fertilized, resulting embryos vitrified

61 McGill Fertility Preservation Center 212 women underwent ovarian stimulation: – –156 stimulation cycles, mature oocytes vitrified – –56 stimulation cycles, mature oocytes fertilized and resulting embryos vitrified

62 Disease Categories for those who Froze Oocytes/embryos Type of Cancer N=183 Breast cancer75 Hematological malignancies47 Brain malignancies15 Gynecological cancers14 Sarcoma11 Desmoid Tumour5 Autoimmune disease9 Melanoma1 Colorectal cancer5 GIT Malignancy1 mean age = 29.7, SD =±5.6

63 Conclusions Current methods of fertility preservation should be considered as investigational Patients and their families should be advised about experimental nature of process Cancer treatments should NOT be compromisedCancer treatments should NOT be compromised

64 Conclusions Fertility preservation is of utmost importance to patients and families of patients undergoing potentially gonadotoxic treatment We provide option to try to preserve fertility potential This hope alone may help in struggle to overcome the disease

65 Proper counseling and shared decision making Fertility preservation center

66 C.K.N: Cancer Knowledge Network. ICRF: Israel Cancer Resreach Fund


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